Ultrafractionation in A7 human malignant glioma in nude mice

Low-dose hyperradiosensitivity (HRS) has been demonstrated in numerous cell lines in vitro, including a number of radioresistant human malignant glioma cell lines such as A7. The aim of our experiment was to show whether HRS can be exploited by using ultrafractionated irradiation (UF) to improve local control of A7 tumours growing in nude mice. Extrapolation of the in vitro results predict a 3.7-fold difference in the efficacy of UF compared with conventional fractionation (CF).

Subcutaneuously growing A7 tumours were irradiated either with UF (126 fractions in 6 weeks, 0.4 Gy per fraction) or CF (30 fractions in 6 weeks, 1.68 Gy per fraction). The total dose was 50.4 Gy in both experimental arms. Fractionated irradiations were given under ambient conditions and followed by graded top-up doses under clamp hypoxia. Endpoints were tumour growth delay and local tumour control 180 days after the end of treatment.

UF resulted in a significant decrease of tumour growth delay and in a significant increase of the top-up TCD(50) compared with CF (40.0 Gy [95% CI 29; 61 Gy] versus 28.3 Gy [24; 35 Gy], p=0.047).

Despite a pronounced HRS phenomenon in vitro, UF was significantly less effective than CF in A7 human malignant glioma in nude mice. These results neither disprove the existence of HRS nor do they exclude a possible clinical value of UF. The findings rather indicate that simplistic extrapolation from results obtained after single-dose exposure or few fractions in vitro is not sufficient to predict outcome of UF in vivo and that comprehensive evaluation of novel treatment options in animal models continues to be an essential requirement for clinical translation.