**4.4 Patient characteristics**

From September 2003 until June 2006, 31 patients were enrolled in this phase II study (16 males and 15 females). Median patient was 58 years (range 37 to 76). Median Karnofsky Performance Status (KPS) was 80, ranging from 60 to 100 (Beauchesne et al., 2010). The median time from diagnosis to the beginning of ultrafractionated radiation therapy was 6 weeks (ranging from 2 to 10 weeks) (Beauchesne et al., 2010). Four patients died before the beginning of irradiation and two decided to revert to the standard radiation therapy regimen after starting (Beauchesne et al., 2010). The radiation course was completed in 22 patients. Multi-focal glioblastoma was diagnosed in seven patients, four of whom received and completed the ultrafractionated regimen (Beauchesne et al., 2010). Neuropathology was review reviewed by a central laboratory and all but one case was diagnosed as glioblastoma as WHO classification, and one case was secondary and classified as anaplastic oligodendroglioma.

#### **4.5 Safety and tolerability**

No toxic death occurred during the ultrafactionated irradiation and no radiation therapy regimen was discontinued. All but three patients (25 patients) received the ultrafractionated irradiation, and 22 completed the course of the treatment (Beauchesne et al., 2010). Two patients with a very large tumor progressed during the radiation therapy, and radiation therapy leading to premature discontinuation after 48 and 56 Gy. The most common adverse event was fatigue, as is frequently observed in standard cranial radiation therapy (Beauchesne et al., 2010). Although the ultrafractionation regimen was a constraint to patients, it was well accepted; only one out of 25 changed his mind during the course of the treatment, and was withdrawn. Overall, the ultrafractionated regimen was well tolerated.

#### **4.6 Survival**

After a median follow-up of 4 years, two of the 31 initial patients were alive (6.5 %). The median survival was 9.53 months (Beauchesne et al., 2010). The OS at 6, 12, 18 and 24 months was respectively 74.19 %, 29.03 %, 19.35 % and 15.48 %. The median PFS was 5.09 months. The PFS at 6, 12, 18, and 24 months was respectively 45.16 %, 12.90 %, 6.45 % and 6.45 % (Beauchesne et al., 2010). No difference was found in the median survival for age and sex: 8.4 months for males vs. 8.9 months for females, 8.4 months for < 55 years vs. 9.5 months for > 55 years (Beauchesne et al., 2010). The trial design allowed the use of fotemustine, a nitrosourea component, as first line of chemotherapy at tumor progression, but patients were treated at the physician's discretion. At the cut-off date, 16 patients had received chemotherapy; fotemustine was given in 14 cases, and temozolomide in 2 (Beauchesne et al., 2010). One patient underwent surgery, and radio-surgery was performed in one case. The response to salvage chemotherapy was not recorded as part of our study.
