Chemotherapy in Glioma

Gliomas are primary brain tumors and include astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas. Currently, treatment of newly diagnosed diffuse adult gliomas exists of surgery, radiotherapy and chemotherapy. We were the first to show a high incidence of progressive MRI lesions in glioblastomas (WHO grade 4 astrocytomas) immediately after combined chemo-radiotherapy with temozolomide, with spontaneous improvement and termed this phenomenon pseudo-progression. Because of these findings it became a general treatment policy to continue temozolomide in case of progressive lesions immediately after chemo-irradiation. Additionally, this thesis focused on the evaluation of classical chemotherapy in adult diffuse glioma in relation to a variety of prognostic molecular tumor characteristics, including isocitrate dehydrogenase 1 (IDH1) mutations, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and loss of chromosomes 1p and 19q).

This thesis has further established the role temozolomide in progressive astrocytomas after radiotherapy and confirmed that IDH1 mutations identify a subgroup of astrocytomas with an improved survival and are strongly correlated with MGMT promotor methylation. Data from this thesis indicated that a more continuous dose dense temozolomide schedule is safe and effective in recurrent glioma, but did not suggest superior efficacy of the dose dense temozolomide schedule, by overcoming tumor resistance mediated by methylation of the MGMT promoter as compared to the standard schedule. The Dutch multicenter phase 2 BELOB study suggests a role of bevacizumab in combination with lomustine in recurrent glioblastoma and justifies further phase 3 studies of this treatment. Our long-term follow-up study in newly diagnosed large oligodendroglial tumors indicated that upfront procarbazine, lomustine and vincristine (PCV) chemotherapy is associated with long (progression free) survival and delays radiotherapy for a considerable period of time, especially in patients with combined 1p/19q loss. Growth kinetics showed an ongoing decrease of the mean tumor diameter years after completion of the PCV chemotherapy.