Molecular stratification and clinical management of adult high-grade glioma: Lessons from the elderly trials


Year:

Session type:

Michael Weller1
1University Hospital Zurich, Zurich, Switzerland

Abstract

Age has been identified as a strong negative prognostic factor for patients with anaplastic gliomas and glioblastoma decades ago. Population-based studies in Europe and the US indicate that elderly patients with high-grade gliomas continue to be treated less intensively than younger patients. Notably biopsy is more often the first surgical intervention and elderly patients receive salvage therapies less frequently. Based on recent randomised trials, new standards of care have emerged in the elderly. The initial diagnostic work-up should include the assessment of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter status by methylation-specific PCR. Patients with MGMT promoter-unmethylated glioblastoma should probably be treated with hypofractionated radiotherapy e.g. 15 x 2.66 Gy to a total dose of 40 Gy. Patients with MGMT promoter-methylated glioblastoma should no longer be treated with radiotherapy alone, but rather with temozolomide at 200 mg/m2 probably until progression or for 12 cycles. Whether temozolomide should be administered alone as initial therapy and radiotherapy be deferred, or combined with hypofractionated radiotherapy up-front, remains a matter of debate. An ongoing NCIC/EORTC intergroup trial investigates combined hypofractionated radiotherapy and concomitant and adjuvant temozolomide chemotherapy with hypofractionated radiotherapy in elderly patients with glioblastoma. This trial will inform about the magnitude of benefit derived from temozolomide in addition to radiotherapy by MGMT status. New trial concepts of the EORTC focus on the addition of the vascular endothelial growth factor (VEGF) antibody, bevacizumab, to these current standards of care since retrospective studies suggest a preferential clinical role for VEGF inhibition in the subpopulation of the elderly. This concept is currently explored in a Swiss phase II trial (ARTE). Meanwhile, molecular studies have provided the first findings which may explain the poor outcome in the elderly, beyond the general issue of less intensive treatment. The most important finding in this regard is the virtual absence of isocitrate dehydrogenase (IDH) mutations in elderly patients with anaplastic astrocytoma and glioblastoma.