alone in patients with anaplastic oligodendroglioma or oligoastrocytoma (Cairncross et al. 2006; van den Bent et al. 2006). Only after a follow-up of 6 years it became obvious that patients with LOH 1p/19q showed a dramatic benefit in OS when treated with radiotherapy and PCV (Cairncross et al. 2013; van den Bent et al. 2013). Hence, the 1p/19q status is not just prognostic but also predictive, requiring the testing for this marker before treatment planning. As for lowgrade glioma, it remains unclear whether PCV alone would achieve similar results and whether temozolomide could safely replace PCV.

3.5.3Gliomatosis Cerebri

Gliomatosis cerebri is a rare and controversial diagnosis and might be revised in future WHO classifications. This tumor cannot be defined by the neuropathologist alone. The diagnosis requires a combination of glioma histology and the radiological involvement of at least three cerebral lobes (Louis et al. 2007).

As this entity is the prototype of an infiltrative tumor, surgical resection is usually no option, and stereotactic biopsy leads to the diagnosis.

Histological features and prognosis are highly variable since any glioma histology together with radiology can lead to the diagnosis. Usually, all patients receive treatment after diagnosis.

Large randomized trials for adjuvant treatment are lacking. Radiotherapy, PCV, and temozolomide are active treatments (Herrlinger 2012; Sanson et al. 2004). Due to the diffuse growth, radiotherapy usually results in whole brain radiotherapy and is therefore frequently postponed. Instead, chemotherapy is frequently recommended for first-line treatment. The NOA-05 trial is one of the few prospective trials on chemotherapy in gliomatosis cerebri (Glas et al. 2011). Chemotherapy with PC (procarbazine + CCNU) resulted in prolonged tumor control in some patients in this trial, and the median OS was only 30 months.

3.6Glioblastoma (WHO Grade IV)

Glioblastoma is the most frequent malignant primary brain tumor. Several studies suggest that the extent of resection is relevant for prognosis, although class I evidence is still lacking (Sanai et al. 2011; Kreth et al. 2013). Surgery using 3D navigation systems and intraoperative monitoring is standard in most centers. With 5-ALA-guided resection and intraoperative MRI, two techniques to improve extent of resection have been evaluated in a randomized controlled setting (Senft et al. 2011; Stummer et al. 2006). Both studies showed an increase of patients with gross total resection and superior survival. Awake surgery is done by some centers but cannot be regarded as a standard for patients with glioblastoma.

The current standard of care was defined in 2005 with the results of the EORTC 26981–22981 NCIC CE.3 (Stupp et al. 2005, 2009). This trial compared radiotherapy, the former standard of care, with radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. Median OS was prolonged from 12.1 to 14.6 months. Two-year survival rate increased from 10.4 to 26.5 %. In addition, a companion paper reported on the predictive value of the MGMT promoter methylation status (Hegi et al. 2005). The benefit of the addition of temozolomide was far lower when the MGMT promotor was not methylated. Patients with a methylated MGMT promotor showed a median OS of 15.3 months when they received radiotherapy alone and 21.7 months after combined treatment. Importantly, the majority of patients had alkylating agent chemotherapy at progression, diluting the survival benefit afforded by temozolomide in the experimental arm. When the MGMT promotor was unmethylated, median OS reached 11.8 and 12.7 months for radiotherapy alone and combined treatment, respectively. This benefit in patients with unmethylated MGMT promotor was small but still significant. Therefore, and because of missing alternatives as well as a certain amount of uncertainty regarding the procedures for testing the MGMT promotor, most patients are treated with a combined radiochemotherapy irrespective of the MGMT promotor status (Weller et al. 2014).

In elderly patients with glioblastoma, the MGMT status is more relevant. The NOA-08 trial randomized patients older than 65 years between radiotherapy alone and temozolomide alone (Wick et al. 2012). For the whole cohort, there was no significant difference in PFS and OS, suggesting that temozolomide is equally active in these patients. When analyzing the subgroups of patients with methylated and unmethylated MGMT promotor, however, significant and clinically relevant differences were observed. In patients with methylated MGMT promotor temozolomide resulted in an event-free survival (EFS) of 8.4 months compared to 4.6 months for radiotherapy. In contrast, in patients with unmethylated MGMT promotor, temozolomide showed an EFS of 3.3 months and radiotherapy of 4.6 months. Similar results were observed in the Nordic trial (Malmstrom et al. 2012). As a result of these studies, treatment planning in older patients depends on MGMT status (Wick et al. 2014; Weller et al. 2012b, 2014). Patients with methylated MGMT promotor should receive temozolomide, either alone or in combination with radiotherapy for patients with a good clinical status. Radiotherapy alone is not sufficient for these patients. When the MGMT promotor is unmethylated, radiotherapy is the therapy of choice. Temozolomide seems to have no or only minimal efficacy in these patients.

In the recurrent situation, no formal standard is established. If possible, second surgery and second radiotherapy are regularly applied even if evidence for efficacy is low (Fogh et al. 2010; Grosu et al. 2005). Regarding chemotherapy, nitrosourea-based protocols and temozolomide are