ESTRO 37 Abstract book

S297

ESTRO 37

France 3 Institut Pasteur, Anatomopathology and Animal models, paris, France 4 Institut Curie, Experimental Radiotherapy Platform, Orsay, France 5 University Paris Sud, IR4M, Orsay, France Purpose or Objective The morbidity of normal tissues continues being the main limitation in radiotherapy. To overcome it, we proposed a novel concept: proton minibeam radiation therapy (pMBRT) [1]. It allies the physical advantages of protons with the normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams (minibeam radiation therapy) [2]. We have recently implemented this technique [3] at a clinical center (Proton therapy center in Orsay) and demonstrated that pMBRT leads to a significant increase of normal tissue tolerances [4] with respect to standard proton therapy. This work aimed at showing that this gain allows using potentially curative doses in the cases of radioresistant tumors, like gliomas. Material and Methods Two groups (n=10) of 7 weeks old male Fischer 344 rats were implanted 5000 RG2 rat glioma cells Intracranially. Half of the animals received a whole brain irradiation (pMBRT), 9 days after tumor inoculation. A clinically relevant proton beam energy (100 MeV) was used. The animals were irradiated in the plateau region. Figure 1 shows a schema of the irradiation settings. The dose distributions were completely inhomogeneous, with areas of very high doses in the minibeam paths (70 Gy in one fraction) and areas of low doses in the spaces between minibeams (around 10 Gy). The clinical status of the animals was evaluated daily. Any rat showing adverse neurological signs related to the tumour growth (loss of appetite, seizures, substantial weight loss among others) in the brain was be humanly killed. A third group (n=8) of normal rats were irradiated (whole brain) in the same configuration and followed for 6 months. A magnetic resonance imaging (MRI) study a 7T small animal MRI was performed 6 months after irradiation.

Conclusion The results of this pilot study suggest that pMBRT widens the therapeutic window for gliomas and might offer a curative option. The fact that a significant tumor control is even with inhomogeneous dose distributions contradicts the classical paradigm of standard radiotherapy and points at the participation of distinct radiobiological mechanisms. [1] Prezado et al. Med. Phys. 40, 031712, 1–8 (2013). [2] Prezado et al., Rad. Research. 184, 314-21 (2015). [3] Peucelle et al., Med. Phys. 42 7108-13 (2015). [4] Prezado et al., Nat. Scie. Reports, in press PV-0570 Proton minibeam radiation therapy (pMBRT): a novel approach to minimize normal tissue damage T.E. Schmid 1,2 , A. Hunger 1 , M. Sammer 3 , E. Zahnbrecher 2 , J. Reindl 3 , K. Ilicic 2 , D. Walsh 3 , C. Greubel 3 , B. Schwarz 3 , J.J. Wilkens 2 , G. Dollinger 3 , S.E. Combs 1,2 1 Helmholtz Zentrum München, Institute of innovative Radiotherapy, Neuherberg, Germany 2 Klinikum rechts der Isar- Technische Universität München, Radiooncology, München, Germany 3 Universität der Bundeswehr München, Institut für angewandte Physik und Messtechnik, Neubiberg, Germany Purpose or Objective In radiation therapy, the maximum dose which can be delivered to a certain tumor is limited by the radiation induced damage in normal tissue surrounding the actual tumor. Proton minibeam radiotherapy aims to minimize normal tissue damage in the entrance channel while keeping tumor control through a homogeneous tumor dose due to channel widening with increasing track length. Acute side effects of proton minibeam irradiation were examined in an in-vivo mouse model to account for immune system, vasculature and higher complexity. In this study, partially widened proton minibeams were simulated as they occur on their way to the tumor within the normal tissue in an in vivo mouse model. Material and Methods A total of six different minibeam sizes were applied to the ear of Balb/c mice using 20 MeV protons. The average dose of 60 Gy was distributed in 4x4 minibeams with beam sizes of σ = 0.09, 0.2, 0.31, 0.45, 0.56 and 0.9 mm and a beam-to-beam distance of 1.8 mm. Inflammatory response, i.e. ear swelling and skin reactions, were monitored for 90 days following irradiation. Results The results show a correlation between the applied beam sizes and the dimension of acute side effects after irradiation. The largest beam sizes lead to significant ear swelling (up to 3-fold), erythema and desquamation 3-4 weeks after irradiation. With decreasing beam sizes, the maximum skin reactions were reduced until almost no ear swelling or other visible skin reactions to the irradiation could be detected. However, all sizes of minibeams were superior to homogeneous Irradiation.

Results Figure 2 shows the survival probability curves (Kaplan- Meyer) for the two tumor bearing animals groups. The controls presented a mean survival time of 20.8 ±0.4. The group receiving pMBRT showed a substantial increase of mean survival time (as today, a factor 5 gain with respect to the controls). The existence of several long term survivals indicates tumor sterilization. The irradiated normal rats exhibited no clinical symptoms for 6 months after irradiation in contrast to rats irradiated in previous studies with lower doses [4]. No substantial damage was observed in the MRI evaluation.