**4.8 Commentaries**

Before this study was conducted, the safety and tolerability of this new regimen of radiation therapy, three doses per day administered at intervals at least 4 hours, were unknown. This was the first time that such an ultrafractionated radiation therapy regimen was clinically

Ultrafractionated Radiation Therapy (3 daily doses of 0.75 Gy) -

**5. Conclusions** 

with a clonogenic assay).

**6. References** 

2.4 Gy, once a day) to inhibit tumor growth.

A New and Promising Radiotherapy Schedule for Glioblastoma Patients 409

The "Low Dose Hypersensitivity" phenomenon has been demonstrated *in vitro* in a number of various human malignant glioma cell lines, when cells were irradiated with single-doses of X-rays from 0.05 to 5 Gy, and focusing on cell survival at doses less than 1 Gy. Interestingly, daily repeated irradiation of cells with low doses compared to irradiation with a single biologically equivalent dose resulted in significantly higher cell kill (as measured

Experiments conducted on glioma xenografts went on to demonstrate that repeated irradiation with low doses (0.8 Gy, 3 times a day) is more effective than a single dose (2 or

Clinical trials on ultrafractionated radiation regimens confirm these experimental results and have proved to be safe and well tolerated. No acute grade 3 and/or 4 CNS toxicity has been observed in such trials. Median progression-free and survival from initial diagnosis have been found to be 5.1 and 9.5 months. When compared with the EORTC/NCIC trial in both PFS and OS multivariate analysis, ultrafractionation showed superiority over radiation therapy alone but not over radiation therapy and temozolomide. Nevertheless, the treatment regimen has proved feasible, well tolerated and deserves to be further evaluated

Athanassiou H, Synodinou M, Maragoudakis E, et al. (2005). Randomized phase II study of

Beauchesne PD, Bertrand S, Branche R, et al. (2003). Human malignant glioma cell lines are

Beauchesne PD, Bernier V, Carnin C, et al. (2010). Prolonged survival for patients with

Beck-Bornholdt HP, Maurer T, Becker S, et al. (1989). Radiotherapy of the

Behin A, Hoang-Xuan K, Carpentier AF, et al. (2003). Primary brain tumours in adults.

Fine HA, Dear KB, Loeffler JS, et al. (1993). Meta-analysis of radiation therapy with and

Hall EJ. (1978). Radiobiology for the radiologist, 2nd ed. Hargestown ; Harper and Row. James CD, Olson JJ. (1996). Molecular genetics and molecular biology advances in brain

without adjuvant chemotherapy for malignant gliomas in adults. *Cancer*, 71, 2585-

temozolomide and radiotherapy compared with radiotherapy alone in newly

newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated

rhabdomyosarcoma R1H of the rat: hyperfractionation–126 fractions applied within

in combination with the current standard concomitant chemotherapy agents.

diagnosed glioblastoma multiforme. *J Clin Oncol*, 23, 2372-2377.

sensitive to low radiation doses. *Int J Cancer*; 105, 33-40.

6 weeks. *Int J Radiation Oncology Biol Phys*, 16, 701–705.

Black PM. (1991a). Brain tumor. Part 2. *N Engl J Med*, 324, 1555-1564. Black PM. (1991b). Brain tumors. Part 1. *N Engl J Med*, 324, 1471-1476. DeAngelis LM. (2001). Brain tumors. *N Engl J Med*, 344, 114-123.

tumors. *Curr Opin Oncol*, 8, 188 –195.

radiation therapy. *Neuro Oncol*, 12, 595-602.

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performed (Beauchesne et al., 2010). The study showed that the regimen is safe, well tolerated and well accepted by the patients. No toxic death occurred and no neurological symptoms evoking a post-radiation therapy leuco-encephalopathy were recorded (Beauchesne et al., 2010). Neither were any abnormal radiological findings suggesting a potential toxic effect of ultrafractionated irradiation noted on cranial MRI. Fatigue, as is usually observed with the standard cranial irradiation, was the main adverse event recorded.

The median survival compares favorably with the best outcomes observed in the recent large randomized studies (Athanassiou et al., 2005; Westphal et al., 2003). Moreover, these studies had included a high percentage of patients with better prognosis (good WHO performance status – young age – resection of tumor – a single tumor), and the adjuvant chemotherapy was systematically administered (Athanassiou et al., 2005; Westphal et al., 2003). The EORTC-NCIC study reported a median survival of 7.85 and 9.4 months respectively for radiation therapy alone and temozolomide/radiotherapy together administered to patients with inoperable glioblastomas (Stupp et al., 2005).

Beauchesne et al's study resulted in both a longer median survival time and higher OS at 24 months (9.53 months – 15.38 % and 7.4 months – 8 % respectively) than the RTOG 90-06 trial (7.4 months and 8 % respectively) (Beauchesne et al., 2010; Scott et al., 1998). Furthermore, there were an unexpectedly high number of long survivors; 19.35 % and 15.48 % at 18 and 24 months. This compares favorably with the 24 months survival in the EORTC-NCIC study which stands at 4.59 % for the radiation therapy alone arm and 10.42 % for the temozolomide/radiation therapy arm (Beauchesne et al., 2010; Stupp et al., 2005). Furthermore half of the patients in the Beauchesne et al trial did not receive a chemotherapy line or other therapy (Beauchesne et al., 2010). It seems reasonable therefore to claim an ultrafractionated radiation therapy regimen may result in better long survival and OS compared with the best results reported in the literature.

These encouraging results support the development of a randomized phase II study to test the efficacy of a concomitant combination of ultrafractionated radiation therapy and temozolomide in no-operable glioblastomas. Beauchesne et al initiated such a study in February 2008 in France to test this new combination of ultrafractionated irradiation and temozolomide. Patients over 18 years of age who are able to give informed consent and have histologically proven, newly diagnosed inoperable and supratentorial glioblastoma are eligible. Three doses of 0.75 Gy are delivered daily at a minimum of 4 hour intervals, 5 days a week for 6 consecutive weeks (67.5Gy). Concomitant chemotherapy consisting of temozolomide is given 7 days per week during the ultrafractionated radiation therapy. After a 4-week break, chemotherapy is resumed with up to 6 cycles of adjuvant temozolomide every 28 days. Tolerability and toxicity are the primary endpoints and survival and PFS the secondary endpoints.

To date 36 patients have been enrolled in this study, 24 men and 12 women with a median age of 62, years and median KPS of 80. The ultrafractionated radiation therapy temozolomide combination has been well tolerated; no acute grade 3 and/or 4 CNS toxicity has been observed and only one grade 4 hematological toxicity has been reported. Two patients progressed during the radiation therapy, and two patients died of pulmonary embolism. Median survival has not yet been reached. Half of the patients have survived for more than one year.
