**4. Clinical trials**

404 Advances in the Biology, Imaging and Therapies for Glioblastoma

(Beauchesne et al., 2003; Pedeux et al., 2003). These experiments show that ultrafractionated irradiation provides a marked benefit compared to a more classical irradiation regimen. It is worth noting that the use of a clinical linear accelerator is more feasible and the ultrafractionated regimen could thus be suitable for clinical treatment (Beauchesne et al.,

> 0,8 2 Tem **Treatment**

Fig. 4. Inhibition of glioma tumor growth following repeated irradiation with low doses. G152 glioma cells injected into the interscapular region of 4-week-old female nude mice (Swiss *nu/nu*). Seventeen days after grafting, mice were exposed either to 0.8 Gy 3 times/day spaced by 4 hr 5 days/week for 2 consecutive weeks or to 2.4 Gy once/day 5

Krause et al tested the ultrafractionated regimen in an animal model grafted with cells derived from the A7 human cell line which expressed the HRS phenomenon (Krause et al., 2003). Cryoprereserved tumor tissue was transplanted subcutaneously onto the backs of ve mice. The tumor with the median volume doubling time was transplanted onto the back of another eight to 12 mice. 1–2 mm pieces of tissue from the median tumor were then transplanted subcutaneously into the right hind leg of the experimental animals (Krause et al., 2003). Irradiation protocols were started daily when the tumours reached a mean diameter of 5 mm, corresponding to a volume of 57 mm3; the ultrafractionated regimen consisted of 26 fractions over 6 weeks (0.4 Gy per fraction, 3 fractions per day, 21 fractions per week, spaced at 6 hour intervals), and conventional treatment consisted of 30 fractions over 6 weeks (1.68 Gy per fraction, once daily, 5 fractions per week) (Krause et al., 2003). A local irradiator was used. Endpoints were tumor growth delay and local tumor control 180 days after the end of the treatment, and for the first 60 days after the end of irradiation. The tumors were measured twice weekly and once weekly thereafter (Krause et al., 2003). The

days/week for 2 consecutive weeks. Tumor size was measured once a week.

2003; Pedeux et al., 2003).

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The ultrafractionated radiation therapy regimen

To translate these *in vitro* and *in vivo* observations into a clinical setting, Beauchesne et al initiated a phase I/II clinical trial using an ultrafractionated radiation therapy protocol (3 times 0.75 Gy for a total of 67.5 Gy) (Beauchesne et al., 2010). The main purpose of this study was to assess the toxicity of the ultrafractionated regimen. This protocol was initiated before concomitant radio-chemotherapy became standard of care. For this pilot trial, the authors purposely selected patients with unfavourable clinical prognostic factors: newly unresectable glioblastoma (Beauchesne et al., 2010).
