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A silver lining on the horizon for glioblastoma
Reflection and Reaction
A silver lining on the horizon for glioblastoma Glioblastoma multiforme is one of the worst diagnoses that a doctor can communicate to a patient; and despite the encouraging news included in the update on the European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups and the National Cancer Institute of Canada (EORTC-NCIC) intergroup study1 published in this issue of The Lancet Oncology, this remains the case. However, the nihilistic attitude toward this diagnosis should begin to dissipate as trials with in-depth pathological investigations continue to hew away at fundamental questions of the ontogenesis and management of this complex and refractory malignant disease. The original report of this trial2 established a new standard of management for glioblastoma multiforme. Patients treated with radiotherapy plus temozolomide had a 37% relative reduction in risk of death compared with those receiving radiotherapy alone (median survival benefit 2·5 months), although patients with a WHO performance status of 2 or those whose only surgery was biopsy had no benefit. At median follow-
CNRI/Science Photo Library
See Articles page 459
Temozolomide revolutionised treatment for glioblastoma
434
up of more than 5 years,1 only 7% of participants in the study are still alive, the relative reduction in the risk of death has improved to 40% for combined treatment, and 5-year survival was about 10% for combined treatment and 2% for radiotherapy alone. Even patients identified with recursive partitioning analysis as having the worst prognosis (age >60 years, surgery limited to biopsy, and baseline mini-mental state examination <26) had statistically significant survival advantages. In an important companion study to the original publication, Hegi and colleagues3 suggested that the survival advantage of combined therapy was entirely attributable to a subset of patients with epigenetic inactivation of MGMT, which encodes an enzyme that repairs methylation of DNA by temozolomide. In the updated report, methylation of the MGMT promoter was the strongest prognostic factor for survival (hazard ratio 0·49) and progression-free survival was better for those with MGMT silencing, although an overall survival benefit was seen for combined treatment irrespective of methylation status. Assays for MGMT promoter methylation are not routine, and although data from this study support combined therapy without knowledge of the size of a potential survival benefit, the updated survival information in this publication makes it increasingly clear that genetic signatures might provide guidance for best clinical management of glioblastoma, just as they do for oligodendroglioma.4 The small benefit of combined therapy for patients without inactivation of MGMT indicates that other treatment approaches are needed for this subset of patients. However, outside of clinical trials, other potential treatments are unavailable. Whether survival disadvantage resulting from MGMT activity can be overcome by an intensive temozolomide schedule after combined treatment might be clarified by results of a phase III trial completed by the Radiation Therapy Oncology Group (RTOG) and EORTC.5 If patients derive benefit from this treatment, determination of MGMT promoter methylation should become a routine diagnostic procedure for patients with glioblastoma to avoid ineffective approaches in first-line management. www.thelancet.com/oncology Vol 10 May 2009
Reflection and Reaction
A study to be opened internationally will test adding bevacizumab to the initial combined therapy of patients with glioblastoma (Gilbert M, Yale Medical School, personal communication). Stratification of patients will include the RTOG recursive partitioning analysis and molecular profiling for MGMT promoter methylation and a panel of genes that are predictive of prognosis.6 This study will include prospective quality of life measurements and test both the apparent value of salvage bevacizumab7 together with standard chemotherapy with radiotherapy and also how well more extensive molecular profiling can predict important outcomes. Multidimensional computer-assisted histopathology of tumour-tissue microarrays of responders and nonresponders will help to focus treatment for glioblastoma in all patients.8 Advances are possible in many areas, including understanding of the perivascular stemcell niche and its role in refractory and aggressive tumours,9 characterisation of microRNA involvement in post-transcriptional modification of gene expression,10 development of better drugs to correct dysregulated signal transduction pathways of growth and angiogenesis, modulation of chemotherapy and radiotherapy resistance, and immunotherapy. Translation of these new treatment ideas continues at a painstakingly slow speed determined not only by academic ingenuity, but also by the economic reality of clinical research. However, the advances are clear in glioblastoma for which there has long been no hope of treating. Current and future generations of neurooncologists need to wisely allocate resources to the
development of entirely new treatment approaches, recognise those worth translating, and effect their actual translation to achieve a cure for patients with glioblastoma. Jonathan P Knisely, Joachim M Baehring Department of Therapeutic Radiology (JPK) and Department of Neurosurgery, Medicine, and Neurology (JMB), Yale University School of Medicine, New Haven, CT, USA [email protected] The authors declared no conflicts of interest. 1
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Stupp R, Hegi ME, Mason WP, et al; on behalf of the European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups and the National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459–66. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987–96. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997–1003. Cairncross G, Jenkins R. Gliomas with 1p/19q codeletion: a.k.a. oligodendroglioma. Cancer J 2008; 14: 352–57. Radiation Therapy Oncology Group. Radiation therapy and temozolomide in treating patients with newly diagnosed glioblastoma or gliosarcoma. http://clinicaltrials.gov/ct2/show/NCT00304031 (accessed Feb 14, 2009). Colman H, Aldape K. Molecular predictors in glioblastoma: toward personalized therapy. Arch Neurol 2008; 65: 877–83. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009; 27: 740–45. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061–68. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 2008; 8: 180–92. Nicoloso MS, Calin GA. MicroRNA involvement in brain tumors: from bench to bedside. Brain Pathol 2008; 18: 122–29.
Could it be that less is more? Why is prophylactic cranial irradiation (PCI) used in small-cell lung cancer (SCLC)? The answer is simple: something seems to be better than nothing. A metaanalysis by Auperin and colleagues1 showed that PCI increases survival for patients with limited-stage small-cell lung cancer (LS-SCLC). A recent randomised trial of PCI versus no PCI for patients with extensivestage small-cell lung cancer (ES-SCLC) came to a similar conclusion.2 Radiation is a very effective treatment that, when applied to a clinically negative brain, will increase the survival for patients with SCLC. www.thelancet.com/oncology Vol 10 May 2009
Unfortunately, the decision to use PCI is not that simple for many radiation oncologists, as the potential neuro-cognitive implications for patients can have lasting effects. In this issue of The Lancet Oncology, Le Péchoux and colleagues3 report the results of PCI 99-01: a large phase-III trial designed to identify an optimum dose and fractionation of PCI for patients with LS-SCLC who have a very good response to chemo-radiotherapy. The premise for this trial—that increasing the PCI dose will decrease the incidence of brain metastasis—was
See Articles page 467
435
A silver lining on the horizon for glioblastoma Glioblastoma multiforme is one of the worst diagnoses that a doctor can communicate to a patient; and despite the encouraging news included in the update on the European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups and the National Cancer Institute of Canada (EORTC-NCIC) intergroup study1 published in this issue of The Lancet Oncology, this remains the case. However, the nihilistic attitude toward this diagnosis should begin to dissipate as trials with in-depth pathological investigations continue to hew away at fundamental questions of the ontogenesis and management of this complex and refractory malignant disease. The original report of this trial2 established a new standard of management for glioblastoma multiforme. Patients treated with radiotherapy plus temozolomide had a 37% relative reduction in risk of death compared with those receiving radiotherapy alone (median survival benefit 2·5 months), although patients with a WHO performance status of 2 or those whose only surgery was biopsy had no benefit. At median follow-
CNRI/Science Photo Library
See Articles page 459
Temozolomide revolutionised treatment for glioblastoma
434
up of more than 5 years,1 only 7% of participants in the study are still alive, the relative reduction in the risk of death has improved to 40% for combined treatment, and 5-year survival was about 10% for combined treatment and 2% for radiotherapy alone. Even patients identified with recursive partitioning analysis as having the worst prognosis (age >60 years, surgery limited to biopsy, and baseline mini-mental state examination <26) had statistically significant survival advantages. In an important companion study to the original publication, Hegi and colleagues3 suggested that the survival advantage of combined therapy was entirely attributable to a subset of patients with epigenetic inactivation of MGMT, which encodes an enzyme that repairs methylation of DNA by temozolomide. In the updated report, methylation of the MGMT promoter was the strongest prognostic factor for survival (hazard ratio 0·49) and progression-free survival was better for those with MGMT silencing, although an overall survival benefit was seen for combined treatment irrespective of methylation status. Assays for MGMT promoter methylation are not routine, and although data from this study support combined therapy without knowledge of the size of a potential survival benefit, the updated survival information in this publication makes it increasingly clear that genetic signatures might provide guidance for best clinical management of glioblastoma, just as they do for oligodendroglioma.4 The small benefit of combined therapy for patients without inactivation of MGMT indicates that other treatment approaches are needed for this subset of patients. However, outside of clinical trials, other potential treatments are unavailable. Whether survival disadvantage resulting from MGMT activity can be overcome by an intensive temozolomide schedule after combined treatment might be clarified by results of a phase III trial completed by the Radiation Therapy Oncology Group (RTOG) and EORTC.5 If patients derive benefit from this treatment, determination of MGMT promoter methylation should become a routine diagnostic procedure for patients with glioblastoma to avoid ineffective approaches in first-line management. www.thelancet.com/oncology Vol 10 May 2009
Reflection and Reaction
A study to be opened internationally will test adding bevacizumab to the initial combined therapy of patients with glioblastoma (Gilbert M, Yale Medical School, personal communication). Stratification of patients will include the RTOG recursive partitioning analysis and molecular profiling for MGMT promoter methylation and a panel of genes that are predictive of prognosis.6 This study will include prospective quality of life measurements and test both the apparent value of salvage bevacizumab7 together with standard chemotherapy with radiotherapy and also how well more extensive molecular profiling can predict important outcomes. Multidimensional computer-assisted histopathology of tumour-tissue microarrays of responders and nonresponders will help to focus treatment for glioblastoma in all patients.8 Advances are possible in many areas, including understanding of the perivascular stemcell niche and its role in refractory and aggressive tumours,9 characterisation of microRNA involvement in post-transcriptional modification of gene expression,10 development of better drugs to correct dysregulated signal transduction pathways of growth and angiogenesis, modulation of chemotherapy and radiotherapy resistance, and immunotherapy. Translation of these new treatment ideas continues at a painstakingly slow speed determined not only by academic ingenuity, but also by the economic reality of clinical research. However, the advances are clear in glioblastoma for which there has long been no hope of treating. Current and future generations of neurooncologists need to wisely allocate resources to the
development of entirely new treatment approaches, recognise those worth translating, and effect their actual translation to achieve a cure for patients with glioblastoma. Jonathan P Knisely, Joachim M Baehring Department of Therapeutic Radiology (JPK) and Department of Neurosurgery, Medicine, and Neurology (JMB), Yale University School of Medicine, New Haven, CT, USA [email protected] The authors declared no conflicts of interest. 1
2
3
4 5
6 7
8
9 10
Stupp R, Hegi ME, Mason WP, et al; on behalf of the European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups and the National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459–66. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987–96. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997–1003. Cairncross G, Jenkins R. Gliomas with 1p/19q codeletion: a.k.a. oligodendroglioma. Cancer J 2008; 14: 352–57. Radiation Therapy Oncology Group. Radiation therapy and temozolomide in treating patients with newly diagnosed glioblastoma or gliosarcoma. http://clinicaltrials.gov/ct2/show/NCT00304031 (accessed Feb 14, 2009). Colman H, Aldape K. Molecular predictors in glioblastoma: toward personalized therapy. Arch Neurol 2008; 65: 877–83. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009; 27: 740–45. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061–68. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 2008; 8: 180–92. Nicoloso MS, Calin GA. MicroRNA involvement in brain tumors: from bench to bedside. Brain Pathol 2008; 18: 122–29.
Could it be that less is more? Why is prophylactic cranial irradiation (PCI) used in small-cell lung cancer (SCLC)? The answer is simple: something seems to be better than nothing. A metaanalysis by Auperin and colleagues1 showed that PCI increases survival for patients with limited-stage small-cell lung cancer (LS-SCLC). A recent randomised trial of PCI versus no PCI for patients with extensivestage small-cell lung cancer (ES-SCLC) came to a similar conclusion.2 Radiation is a very effective treatment that, when applied to a clinically negative brain, will increase the survival for patients with SCLC. www.thelancet.com/oncology Vol 10 May 2009
Unfortunately, the decision to use PCI is not that simple for many radiation oncologists, as the potential neuro-cognitive implications for patients can have lasting effects. In this issue of The Lancet Oncology, Le Péchoux and colleagues3 report the results of PCI 99-01: a large phase-III trial designed to identify an optimum dose and fractionation of PCI for patients with LS-SCLC who have a very good response to chemo-radiotherapy. The premise for this trial—that increasing the PCI dose will decrease the incidence of brain metastasis—was
See Articles page 467
435