In randomized clinical trials (Table 16.1), different doses and regimes of radiation therapy (RT) have been applied: higher dose (59.4 Gy, 64.8 Gy) or—in grade II gliomas—lower dose (45 Gy, 50.4 Gy). The randomized multicenter phase III trial EORTC 22844 [10] investigated the impact of low-dose versus high-dose radiation therapy in patients with low-grade gliomas. The primary endpoint was median overall survival. Importantly, quality of life was assessed in both arms too. There was no difference in median overall survival, but quality of life was better in the low-dose radiation group. Another trial group compared different radiation dosages: In the NCCTG/RTOG/ECOG trial, high-dose (64.8 Gy) versus low-dose RT was investigated. Median overall survival was similar, but patients in the high-dose group had significant reduction of scores in the mini-mental status examination. Both trials suggest, therefore, that low-dose RT leads to similar progression-free and overall survival with more stable quality of life and mini-mental status examinations. In WHO grade II tumors, the next arising question was whether the onset of RT after complete resection could be delayed. This question was addressed in the EORTC 22845 trial, where RT, a dosage of 54 Gy, was either administered immediately after resection or at next tumor progression. Median progression-free survival after immediate RT was 5.3 years compared with 3.4 years with delayed RT. Yet, median overall survival was not significantly different (7.4 years in immediate RT versus 7.2 years in delayed RT) [11]. A similar patient population is represented in a subgroup of the RTOG 9802 trial, i.e., patients (n = 111) under the age of 40 years and with macroscopic complete resection as verified by postoperative MRI. These patients did not receive any further therapy after resection, and 48% had progression at 5 years after resection [12].

Combinations of RT with chemotherapy have been investigated in grade II and grade III glioma, and RT was either combined with PCV (usually in earlier trials) or TMZ.

The RTOG 9802 trial compared a sequential therapy of RT (54 Gy) followed by PCV (maximum 6 cycles) versus RT (54 Gy) alone in patients with low-grade glioma with clinical risk factors (defined in this trial as age >40 years or subtotal resection). Both PFS and MOS were significantly prolonged with RT → PCV, mainly in patients with histology of oligodendroglioma. The authors’ conclusion was that RT followed by PCV is superior to RT alone in patients with low-grade glioma, age >40 or incomplete resection leading to practice change in clinical routine [13].

At progression, all three therapeutic modalities surgery, chemotherapy, or RT will in principle be reconsidered. The choice of treatment modality depends on several clinical factors including patient’s wish, KPS, neuroanatomical site of progression, latency between first RT and a potential second RT, chemotherapy regimen at primary diagnosis, and treatment-related toxicities. The impact of re-resection has not been prospectively evaluated; subgroup analysis of glioblastoma trials suggests that re-resection is beneficial only if complete re-resection at progression is feasible [14]. If a postoperative watchful waiting strategy was considered and safe maximal re-resection is not feasible, RT will be evaluated. For patients who have a progression of their disease after RT → PCV, salvage chemotherapy with TMZ is considered.