Probing spatiotemporal fractionation on the preclinical level

In contrast to conventional radiotherapy, spatiotemporal fractionation (STF) delivers a distinct dose distribution in each fraction. The aim is to increase the therapeutic window by simultaneously achieving partial hypofractionation in the tumour along with near uniform fractionation in normal tissues. STF has been studied in silico under the assumption that different parts of the tumour can be treated in different fractions. Here, we develop an experimental setup for testing this key assumption on the preclinical level using high-precision partial tumour irradiation in an experimental animal model. We further report on an initial proof-of-concept experiment. We consider a reductionist model of STF in which the tumour is divided in half and treated with two complementary partial irradiations separated by 24 h. Precise irradiation of both tumour halves is facilitated by the image-guided small animal radiation research platform X-RAD SmART. To assess the response of tumours to partial irradiations, tumour growth experiments are conducted using mice carrying syngeneic subcutaneous tumours derived from MC38 colorectal adenocarcinoma cells. Tumour volumes were determined daily by calliper measurements and validated by CT-volumetry. We compared the growth of conventionally treated tumours, where the whole tumour was treated in one fraction, to the reductionist model of STF. We observed no difference in growth between the two groups. Instead, a reduction in the irradiated volume (where only one half of the tumour was irradiated) resulted in an intermediate response between full irradiation and unirradiated control. The results obtained by CT-volumetry supported the findings of the calliper-derived measurements. An experimental setup for precise partial tumour irradiation in small animals was developed, which is suited to test the assumption of STF that complementary parts of the tumour can be treated in different fractions on the preclinical level. An initial experiment supports this assumption, however, further experiments with longer follow-up and varying fractionation schemes are needed to provide additional support for STF.