histology, and absence of a neurological deficit. Patients with two or fewer unfavorable factors are low-risk patients where therapy might be postponed unless their tumor is located in eloquent brain areas or patients suffer from untreatable epilepsy. Patients with three or more risk factors have dismal prognosis and might be treated immediately unless gross total resection was possible. In these cases, therapy might still be postponed. Chemotherapy also has activity in diffuse astrocytoma (Pace et al. 2003; Quinn et al. 2003; Brada et al. 2003). It is well established for patients who progressed after initial radiotherapy and can be an alternative as initial treatment in some patients. PCV (procarbazine, CCNU, and vincristine) and temozolomide seem to be comparable regarding efficacy with a better toxicity profile for temozolomide.

Recently, the updated results of the RTOG 9802 trial have been presented, although not published in detail yet (Shaw et al. 2012). This trial compared 54 Gy of radiotherapy with 54 Gy of radiotherapy followed by adjuvant chemotherapy with six cycles of PCV. In this regimen, procarbazine, CCNU, and vincristine are combined to a 6-week cycle. This trial included high-risk patients with low-grade glioma > 40 years of age and/or less than total resection. Median OS increased from 7.8 to 13.3 years in the combination therapy group although, interestingly, 77 % of the patients that progressed after radiotherapy had received salvage chemotherapy. A detailed analysis on histology subtypes and especially on molecular markers is lacking.

Whether these rather low-threshold criteria to define highrisk patients will translate to everyday practice is under debate. Further, it remains unanswered whether PCV alone would be equivalent and whether temozolomide could safely replace PCV in combination with radiotherapy. Therefore, many centers recommend the combination of radiotherapy and PCV.

3.4.2Oligodendroglioma

and Oligoastrocytoma (WHO Grade II)

After resection or diagnostic biopsy, the considerations for adjuvant treatment are similar to those for astrocytomas. The prognostic factors defined by the EORTC and mentioned above also apply to oligodendroglioma and oligoastrocytoma. As oligodendroglial tumors more often respond to chemotherapy, this is a more common choice for initial treatment in many centers (van den Bent et al. 1998, 2003). Nonetheless, the emerging standard of care is radiotherapy followed by chemotherapy with PCV according to the RTOG 9802 trial (Shaw et al. 2012).

3.5Anaplastic Glioma (WHO Grade III)

In contrast to low-grade gliomas, adjuvant treatment is mandatory for patients with anaplastic glioma. The limitations of the current WHO classification are obvious in these tumors

as mentioned above. Molecular markers have already entered diagnostic workup and therapeutic decision making (Weller et al. 2014).

3.5.1Anaplastic Astrocytoma (WHO Grade III)

For adjuvant treatment, radiotherapy (60 Gy) was traditionally applied. According to the results of the NOA-04 trial, primary chemotherapy with temozolomide or with PCV seems to be equivalent regarding PFS and OS (Wick et al. 2009). Many brain tumor centers treat patients with anaplastic astrocytomas with radiochemotherapy according to the EORTC NCIC protocol with concomitant temozolomide and six cycles of adjuvant temozolomide. While reasonable, the evidence for this approach is limited and might be provided by the CATNON trial (EORTC 26053–22054). In this ongoing trial, the addition of temozolomide to first-line radiotherapy of anaplastic gliomas without 1p/19q deletion (mostly anaplastic astrocytoma) will be evaluated. In a 2 × 2 design, this study compares radiotherapy alone with radiotherapy plus concomitant temozolomide, radiotherapy plus adjuvant temozolomide, and radiotherapy plus concomitant and adjuvant temozolomide.

In the recurrent situation, treatment is less firmly established, and randomized controlled trials are rare. Second surgery might be an option if possible. Further treatment will depend on first-line treatment. Patients that progress after radiotherapy will be treated with either temozolomide chemotherapy or nitrosourea-based chemotherapy. If firstline treatment consisted of chemotherapy, radiotherapy is an option. Depending on availability, bevacizumab is often applied at progression after radiotherapy and alkylating chemotherapy, with modest PFS rates at 6 months (Weller et al. 2014).

3.5.2Anaplastic Oligodendroglioma

and Oligoastrocytoma

Radiotherapy has long been the standard of care in anaplastic oligodendroglioma and anaplastic oligoastrocytoma. However, these tumors not just frequently respond to radiotherapy, but also to chemotherapy. Especially in tumors with loss of 1p and 19q (LOH 1p/19q), PCV chemotherapy shows response rates of up to 100 % (Cairncross et al. 1994; Buckner et al. 2003). The NOA-04 trial showed that radiotherapy, PCV chemotherapy, and temozolomide are comparable in first-line treatment (Wick et al. 2009). Therefore, many centers recommended temozolomide as first-line therapy in the past, as it shows a superior tolerability profile compared to PCV. The sequence of therapeutic options (RT, PCV, TMZ) was the main focus in this trial.

In 2013, the long-term results of two large randomized controlled trials were published. Both the RTOG 9402 and the EORTC 26951 trial evaluated the combination of radiotherapy and PCV chemotherapy compared to radiotherapy