J G Cairncross

University of Toronto, Toronto, Ontario, Canada

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Publications (171)1182.95 Total impact

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    ABSTRACT: 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 particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide. Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy. An expression signature dominated by HOX genes, which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). This association could be validated in an independent data set. Provocatively, the HOX cluster was reminiscent of a "self-renewal" signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia model. The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion, and innate immune response. This study provides first clinical evidence for the implication of a "glioma stem cell" or "self-renewal" phenotype in treatment resistance of glioblastoma. Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and respective marker development for individualized treatment and patient selection.
    Journal of Clinical Oncology 07/2008; 26(18):3015-24. · 18.04 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    The Lancet Oncology 02/2008; 9(1):29-38. · 25.12 Impact Factor
  • Roger Stupp, J. Gregory Cairncross
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    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.
    12/2007: pages 223-231;
  • Rebecca A Betensky, David N Louis, J Gregory Cairncross
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    ABSTRACT: Subjects in tumour studies are often misclassified with respect to histologic features that are not routinely recorded in diagnostic reports and that display heterogeneity within tumours. Pathologic analysis of the tumours may miss the feature of interest if the pathologist was not alerted to detail the microscopic feature of interest or if it is not present in the selected specimens. In this setting, only the subjects for whom the outcome is not found are potentially misclassified. Analyses of associations between the observed, potentially misclassified, outcome and a second outcome are invalid if the probability of misclassification depends on the second outcome. Three natural tests of association based on the observed data depend on different numbers of nuisance parameters. Most promising is a test based on the ratio of proportions of the observed feature. We illustrate this test using a study of the association of imaging parameters with genetic features in subjects with oligodendroglioma, a common brain tumour. In this study, calcification, a feature related to the imaging parameters, was potentially misclassified as not present.
    Statistics in Medicine 12/2007; 26(26):4808-16. · 2.04 Impact Factor
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    ABSTRACT: Anaplastic oligodendroglioma is a malignant brain tumor uniquely sensitive to treatment with both chemotherapy and radiotherapy. There are few prospective clinical trials for newly diagnosed patients and multiple approaches to the treatment of these patients. This study explored the recommended treatment offered by experts in neuro-oncology. A Web-based survey was developed and distributed to 800 members of the Society of Neuro-Oncology (SNO) who had an e-mail address listed with SNO. Questions addressed use of molecular genetic information and treatment recommendations. A total of 99 clinical SNO members (20%) responded. The majority reported practicing at an academic center in the United States. Two-thirds of respondents see more than five patients with newly diagnosed anaplastic oligodendroglioma annually. Molecular genetic testing was requested for more than 75% of patients, and the results significantly influenced treatment recommendations (p = 0.000003). Regardless of molecular genetic status, the most commonly recommended treatment was the use of concurrent temozolomide and radiotherapy followed by adjuvant temozolomide (18%-34%). The current survey demonstrates that although neuro-oncologists have embraced the use of molecular genetic studies in newly diagnosed anaplastic oligodendroglioma, treatment recommendations vary widely and are often independent of the molecular data.
    Neuro-Oncology 08/2007; 9(3):314-8. · 6.18 Impact Factor
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    ABSTRACT: This is one of the few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in brain cancer patients. Baseline HRQOL scores (from the EORTC QLQ-C30 and the Brain Cancer Module (BN 20)) were examined in 490 newly diagnosed glioblastoma cancer patients for the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap re-sampling procedure and the computation of C-indexes and R(2)-coefficients were used to try and validate the model. Classical analysis controlled for major clinical prognostic factors selected cognitive functioning (P=0.0001), global health status (P=0.0055) and social functioning (P<0.0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings. C-indexes and R(2)-coefficients, which are measures of the predictive ability of the models, did not exhibit major improvements when adding selected or all HRQOL scores to clinical factors. While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor in cancer patients.
    British Journal of Cancer 08/2007; 97(3):302-7. · 5.08 Impact Factor
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    ABSTRACT: To evaluate the hypothesis that adults with partially resected (PR<50% resection) supratentorial low-grade glioma (LGG) benefit from higher doses of radiation. Patients receiving post-operative radiation for WHO grade I-II LGG at the University of Western Ontario between 1979 and 2001 were studied. Patient characteristics evaluated included: age, gender, symptom duration>30 days, seizures at presentation, Karnofsky performance status (KPS)<70, astrocytoma pathology (AS), and radiation dose. A Cox proportional hazard regression model was constructed to test the influence of radiation dose. One hundred and seven patients were analyzed. Patients who had PR were not significantly different from those with STR (subtotal/total resection) in terms of patient characteristics. Median survival (MST) of PR patients who received<or=50 Gy was 16.5 months while those who received>50 Gy had a MST of 109.2 months. The interaction of radiation dose and extent of resection was tested after controlling for other patient factors by Cox regression model. The interaction was highly significant for both OS and PFS (P=0.013 and P=0.003, respectively). This model remained significant after excluding six patients receiving doses<42 Gy (OS, P=0.024, and PFS, P=0.001). The outcome for patients with LGG is dependent on extent of tumor resection and radiation dose. Patients with PR should be considered for higher radiation dose schedules (>50 Gy). Future trials on therapeutic strategies for LGG should consider stratification of patients by extent of tumor resection. Our data suggests that one dose does not fit all.
    Journal of Neuro-Oncology 04/2007; 82(2):165-70. · 3.12 Impact Factor
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    Michael D Blough, Magdalena C Zlatescu, J Gregory Cairncross
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    ABSTRACT: Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter (i.e., gene silencing) occurs in 40% to 50% of patients with glioblastoma and predicts benefit from temozolomide chemotherapy; when unmethylated, MGMT repairs DNA damage induced by temozolomide, contributing to chemoresistance. In this study, we tested the hypothesis that MGMT is regulated by p53 in astrocytic cells, the precursors of which may give rise to glioblastoma. p53 is of interest because, in addition to often being mutated in glioblastoma, inactivation sensitizes some astrocytoma cell lines to temozolomide. MGMT expression was examined in neonatal murine astrocytes and SF767 human astrocytic glioma cells following p53 inactivation by knockout (murine only) or RNAi methods. MGMT mRNA and protein were detected in murine wild-type p53 astrocytes. However, in knockout murine astrocytes and wild-type cells in which p53 was inhibited by RNAi, MGMT expression was reduced by >90%. This effect of p53 on MGMT expression was unrelated to MGMT promoter methylation-in both wild-type and p53-null astrocytes, the MGMT promoter was unmethylated. In wild-type astrocytes, the p53 protein localized to a regulatory region of the MGMT promoter. In SF767 human astrocytic glioma cells, transient knockdown of p53 led to the down-regulation of MGMT gene expression. In murine astrocytes and SF767 cells, p53 regulates MGMT expression without affecting promoter methylation; in astrocytes, this effect may be due to direct binding of p53 to the MGMT promoter. These results imply that the best use of temozolomide requires a thorough understanding of MGMT regulation.
    Cancer Research 02/2007; 67(2):580-4. · 8.65 Impact Factor
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    ABSTRACT: Texture analysis is an important tool for quantitative assessment of medical signals and images. In particular, texture characteristics can help classify and segment specific types of pathology. Often, texture features are extracted from co-occurrence measures of small neighborhoods of pixels. However, methods based on co-occurrence statistics have been largely unsuccessful at differentiating between benign and malignant tissues. We present a texture analysis approach for magnetic resonance images based on local spectral analysis using the S-transform. Our technique produces a texture curve for each pixel in an image that contains spatial frequencies up to the Nyquist frequency. We have successfully used this approach to examine texture characteristics of oligodendroglioma brain tumors. Using our approach, we are able to classify chemosensitive and chemoresistant tumors with high sensitivity and specificity. Texture analysis of magnetic resonance images based on the S-transform may allow improved diagnosis and monitoring of neurological pathology.
    01/2007: pages 311-321; The Fields Institute Communications Series.
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    ABSTRACT: To determine the response rate, time to disease progression, survival, and toxicity of intravenous carboplatin and chronic oral high-dose tamoxifen in patients with recurrent malignant gliomas. Patients with histological confirmation of recurrent malignant gliomas were eligible for this multicenter phase II trial. Treatment consisted of 400 mg/m2 carboplatin intravenously every 4 weeks and oral high dose chronic tamoxifen (80 mg bid in women and 100 mg bid in men). Twenty seven patients met the eligibility criteria and were evaluable for response. The histological subtypes were: 16 (59%) glioblastoma multiforme (GBM), malignant astrocytoma (5 patients), malignant mixed glioma (5 patients), and glioblastoma/gliosarcoma (1 patient). Twenty-two patients (82%) had an ECOG performance status of 0 or 1. No complete responses were observed, 4 patients (15%) achieved a partial response, and 14 patients (52%) had stable disease. Median time to progression was 3.65 months (95%CI 2.56, 4.83). Median overall survival was 14.09 months (95%CI 7.06, 19.91). One patient with a recurrent GBM had a sustained partial response and is progression free 81 months since starting treatment. Another patient with mixed malignant oligoastrocytoma also had a prolonged partial response (lasting 63 months) and is alive 84 months after treatment for recurrence. The most frequently reported grade 3 or 4 toxicities were fatigue (19%), nausea (11%) and anorexia (11%). Carboplatin and high dose tamoxifen has similar response rates to other regimens for recurrent malignant gliomas and are probably equivalent to those found using tamoxifen as monotherapy. Long-lasting periods of disease free survival in some patients (particularly those with malignant mixed oligo astrocytomas) were found.
    Journal of Neuro-Oncology 08/2006; 78(3):311-6. · 3.12 Impact Factor
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    ABSTRACT: We previously reported a phase 2 trial of 69 patients with newly diagnosed anaplastic or aggressive oligodendroglioma who were treated with intensive procarbazine, CCNU (lomustine), and vincristine (PCV) followed by high-dose thiotepa with autologous stem cell rescue. This report summarizes the long-term follow-up of the cohort of 39 patients who received high-dose thiotepa with autologous stem cell support. Thirty-nine patients with a median age of 43 (range, 18-67) and a median KPS of 100 (range, 70-100) were treated. Surviving patients now have a median follow-up of 80.5 months (range, 44-142). The median progression-free survival is 78 months, and median overall survival has not been reached. Eighteen patients (46%) have relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with risk of relapse. Persistent nonenhancing tumor at transplant was identified in our initial report as a significant risk factor for relapse; however, long-term follow-up has not confirmed this finding. Long-term neurotoxicity has developed only in those patients whose disease relapsed and required additional therapy; no patient in continuous remission has developed a delayed neurologic injury. This treatment strategy affords long-term disease control to a subset of patients with newly diagnosed anaplastic oligodendroglioma without evidence of delayed neurotoxicity or myelodysplasia.
    Neuro-Oncology 05/2006; 8(2):183-8. · 6.18 Impact Factor
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    ABSTRACT: Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and first-line administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neuro-oncology practice.
    The Oncologist 03/2006; 11(2):165-80. · 4.10 Impact Factor
  • Warren P Mason, J Gregory Cairncross
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    ABSTRACT: Glioblastoma multiforme is the most common primary brain tumor in adults. Until recently, the standard of care consisted of maximal surgical resection followed by external beam radiotherapy. The role of adjuvant chemotherapy for newly diagnosed glioblastoma has been controversial; most of the numerous randomized phase III trials conducted over the past 40 years have failed to show a statistically significant and clinically meaningful survival advantage for patients randomized to the chemotherapy arm. Consequently, the choices of chemotherapeutics for patients with glioblastoma have been limited, and cytotoxic treatment regimens have usually included a nitrosourea. Temozolomide, a relatively new orally administered methylating agent, has demonstrable activity in glioma. A recent trial conducted under the auspices of the European Organization for the Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has defined a role for temozolomide in the initial management of glioblastoma. A companion correlative tumor-biology study has identified epigenetic silencing of the promoter of the gene that encodes MGMT (O6-methylguanine-DNA methyltransferase) in tumor specimens as a strong and independent prognostic factor for survival among patients with a newly diagnosed glioblastoma, as well as a predictor of survival benefit from chemoradiotherapy with temozolomide. This review briefly summarizes the development of temozolomide as a therapy for patients with malignant brain tumors, emphasizing recent trials that have established a new standard of care for patients with glioblastoma and speculating on how these advances might influence future therapeutic investigations for malignant primary brain tumors.
    Nature Clinical Practice Neurology 01/2006; 1(2):88-95. · 7.64 Impact Factor
  • G Wei Xu, Joe S Mymryk, J Gregory Cairncross
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    ABSTRACT: p53 inactivation sensitizes U87MG astrocytic glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ), drugs used clinically to treat high-grade astrocytomas. In this report, we examined the effect of p53 inactivation on the chemosensitivity of two additional human astrocytic glioma cell lines, D54 and A172, in order to assess whether sensitization is a general property of astrocytic tumor cells. Compared to control cells with intact p53 function, derived lines in which p53 was inactivated displayed significantly reduced clonogenic survival after exposure to BCNU and TMZ. Sensitization to both BCNU and TMZ was associated with failure of p21(WAF1) induction, lack of a sustained G2 cell cycle arrest and significant tumor cell death. These findings suggest that enhanced sensitivity to BCNU and TMZ is a general property of human astrocytic glioma cells in which p53 was disrupted. In contrast, p53 inactivation rendered D54 and U87MG cells significantly more resistant to cis-dichlorodiamminoplatinum (CDDP), another chemotherapeutic to which high-grade astrocytomas sometimes respond. These results indicate that p53 status influences the chemosensitivity of astrocytic glioma cells in a drug-type specific manner, a finding that may have implications for the selection of drug treatments for patients with astrocytic gliomas.
    Journal of Neuro-Oncology 10/2005; 74(2):141-9. · 3.12 Impact Factor
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    G Wei Xu, Joe S Mymryk, J Gregory Cairncross
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    ABSTRACT: Pifithrin-alpha (PFTalpha) is a small molecule inhibitor of p53. By reversibly blocking apoptosis in response to DNA damage, PFTalpha protects normal cells from lethal doses of gamma-radiation (Komarov et al., Science, 1999;285:1733-7). We examined the effect of PFTalpha on the chemosensitivity of a human cancer in which cell cycle arrest, not apoptosis, is the principle cellular consequence of p53 activation. This was of interest because E6 silencing of p53 sensitizes U87MG astrocytic glioma cells to BCNU and temozolomide (TMZ), cytotoxic drugs that are modestly helpful in the treatment of aggressive astrocytic gliomas. We observed that exposure of U87MG cells to PFTalpha before cytotoxic chemotherapy attenuated p53-mediated induction of p21WAF1 protein levels, sensitizing U87MG cells to BCNU and TMZ. Sensitization of U87MG cells was associated with G1 arrest, delayed entry into S-phase and decreased repair of DNA damage by BCNU. Our findings suggest that in addition to protecting normal cells from the toxic effects of radiation and chemotherapy, small molecule inhibitors of p53, like PFTalpha, might play a role in clinical oncology by sensitizing certain resistant cancers to cytotoxic chemotherapies.
    International Journal of Cancer 09/2005; 116(2):187-92. · 6.20 Impact Factor
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    ABSTRACT: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.
    New England Journal of Medicine 03/2005; 352(10):997-1003. · 54.42 Impact Factor
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    ABSTRACT: Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.
    New England Journal of Medicine 03/2005; 352(10):987-96. · 54.42 Impact Factor
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    RA Brown, MC Zlatescu, JG Cairncross, JR Mitchell
    Visualization, Imaging, and Image Processing; 01/2005
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    ABSTRACT: In modern clinical neuro-oncology, no variable affects therapeutic decisions and prognostic estimation more than tumor classification. The most widely used method of brain tumor classification is that of the World Health Organization (WHO), most recently revised in 2000 (51), which is based on microscopic examination of tissue by a pathologist. The WHO classification divides nervous system tumors into many nosological entities (Table 1) and assigns a grade of I to IV, grade I being benign and grade IV being highly malignant. Although, in the majority of cases, the assignment of tumors in the WHO classification system is relevant and appropriate, unfortunately there are many situations in which this classification is problematic, primarily because pathological diagnosis remains quite subjective (67). For example, some brain tumors are difficult to place neatly into one of the categories. For others, the histological diagnosis and corresponding predicted clinical behavior do not concur with the actual clinical course. Finally, it is doubtful that the current histopathological system alone will accurately predict patient response to targeted therapies once available. As such, information capable of augmenting the WHO system could result in marked improvements in the current approach to brain tumor classification.
    12/2004: pages 33-53;
  • International Journal of Radiation OncologyBiologyPhysics 09/2004; 60. · 4.52 Impact Factor

Publication Stats

14k Citations
1,182.95 Total Impact Points


  • 1999–2014
    • University of Toronto
      • Department of Medicine
      Toronto, Ontario, Canada
  • 1996–2014
    • The University of Calgary
      • • Department of Clinical Neurosciences
      • • Faculty of Medicine
      • • Hotchkiss Brain Institute
      Calgary, Alberta, Canada
  • 1987–2011
    • The University of Western Ontario
      • • Department of Clinical Neurological Sciences
      • • Division of Radiation Oncology
      • • Department of Oncology
      • • Department of Microbiology and Immunology
      London, Ontario, Canada
  • 2008
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands
    • Brain Canada
      Montréal, Quebec, Canada
  • 2007–2008
    • Tom Baker Cancer Centre
      Calgary, Alberta, Canada
  • 2002–2007
    • Harvard University
      • Department of Biostatistics
      Cambridge, MA, United States
  • 1998–2007
    • Memorial Sloan-Kettering Cancer Center
      • Department of Neurology
      New York City, NY, United States
    • Salk Institute
      • Molecular Neurobiology Laboratory
      La Jolla, CA, United States
    • Stanford University
      • Department of Neurology and Neurological Sciences
      Stanford, CA, United States
  • 2006
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 1999–2003
    • Massachusetts General Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 1990–2003
    • Regional Integration Cancer Center
      Мендоса, Mendoza, Argentina
  • 2001
    • Université de Sherbrooke
      Sherbrooke, Quebec, Canada
  • 2000
    • American Academy of Neurology
      Saint Paul, Minnesota, United States
  • 1997
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1995–1996
    • University of Minnesota Twin Cities
      • Department of Neurology
      Minneapolis, MN, United States
  • 1994
    • Victoria General Hospital
      Winnipeg, Manitoba, Canada