ESTRO 38 Abstract book

S20 ESTRO 38

1 Maastricht university, Department of Precision Medicine‐ the m‐lab‐ gUow ‐ school for Oncology and Developmental biology, Maastricht, The Netherlands Abstract text Several clinical studies have shown the possibilities to give a higher dose to certain hypothetically more radioresistant tumour sub-volumes, typically with high accumulation of FDG or a hypoxia tracer. We have tested the therapeutic efficacy of dose-painting (DP) strategies, i.e. targeted dose escalation and dose redistribution, in a rat syngeneic rhabdomyosarcoma model based on FDG uptake [1]. Our data indicate that, while dose escalation to high FDG uptake sub-volume was not superior to the same dose increase in low FDG uptake areas, dose redistribution was even detrimental, consistent with the hypothesis that tumor response is dependent on the minimum intratumoral dose. Interestingly, in the same tumour model dose escalation to the hypoxic sub-volume, as determined by the highest uptake of HX4 hypoxia tracer, resulted in worse tumour response than the same dose increment to the non-hypoxic sub-volume [2]. This data suggests that dose to the tumour bulk should be sufficient to inactivate non-hypoxic cells. It might be difficult to achieve clinically sufficient dose escalation to eradicate tumour cells in hypoxic tumor sub- volume. Therefore, we moved beyond the traditional DP approaches combining hypoxia-targeted drugs with inverse dose-painting of hypoxic sub-volume and thus offering, in our view, more efficient utilization of radiation, i.e. radiation boost to non-hypoxic tumour areas with simultaneous inactivation of hypoxic tumour cells by a HAP. Indeed, our results support targeted dose escalation to non-hypoxic sub-volume with no/low activity of HAPs. This strategy applies on average a lower radiation dose and is as effective as uniform dose escalation to the entire tumour. Routine implementation particularly of hypoxia PET imaging in the clinic is problematic because it is expensive, labor intensive, not attractive for the patient, or even not accessible. Therefore, partial non-targeted tumour irradiation with high dose in combination with immunotherapy might be a new alternative approach to dose-painting, which is currently being tested in our laboratory. It is expected that partial tumour irradiation enables delivery of high doses to tumor sub-volumes reducing normal tissue injury, causes less total damage to intratumoral vasculature permitting immune cells infiltration and provides stronger induction of immunogenic cell death releasing antigens and stimulants to immune system, while immunotherapy boosts anti- tumour immune response with systemic therapeutic potential. References: 1. Trani D, Yaromina A, Dubois L, Granzier M, Peeters SG, Biemans R, Nalbantov G, Lieuwes N, Reniers B, Troost EE, Verhaegen F, Lambin P. Preclinical Assessment of Efficacy of Radiation Dose Painting Based on Intratumoral FDG-PET Uptake. Clin Cancer Res. 2015;21(24):5511-8. 2. Yaromina A, Granzier M, Biemans R, Lieuwes N, van Elmpt W, Shakirin G, Dubois L, Lambin P. A novel concept for tumour targeting with radiation: Inverse dose-painting or targeting the "Low Drug Uptake Volume". Radiother Oncol. 2017;124(3):513-520.

1 University of Zurich, Applied Radiobiology, Zurich, Switzerland

Purpose or Objective Reactive oxygen species are generated in response to ionizing radiation (IR) and produce amongst others irreversible DNA double-strand breaks. This IR-induced cytotoxic effect is less abundant under hypoxia and thus hypoxic cells are more resistant to IR. Hence, reoxygenation of the hypoxic tumor fraction by a combined treatment modality with a pharmaceutical agent is of high interest to reduce the required dose of IR and thereby to further minimize normal tissue toxicity. Here we investigated the combined treatment modality of the novel anti-hypoxia compound myo -inositol trispyrophosphate (ITPP) in combination with IR for the treatment of murine colorectal liver metastases (CLM). Material and Methods ITPP was developed as an effector of hemoglobin lowering the oxygen/hemoglobin affinity thereby resulting in an enhanced release of oxygen e.g. in hypoxic tumors. Murine colorectal cancer cells (MC38) were injected either subcutaneously or orthotopically in the right lateral liver lobe of female C57BL/6 mice. Mice were treated with a previously identified regimen of ITPP (2x 3g/kg, neoadjuvant) alone and in combination with single fractions of IR ranging from 2.5 to 30 Gy. Tumor detection and irradiation were performed by contrast-enhanced CT and a small-animal radiotherapy (X-Rad225Cx), respectively. Tumor volumes were probed either by caliper measurements (subcutaneous tumors) or by serial MRI. Liver functional parameters in the blood serum were assessed 7 weeks upon irradiation. Results Treatment with ITPP alone did not reduce the growth rate of subcutaneous tumors as compared to vehicle treatment. However, ITPP in combination with a single high dose fraction of IR (12 Gy) significantly delayed tumor growth in comparison to irradiation alone. Selective intraportal injection of colorectal cancer cells yields a high rate in colorectal liver metastasis formation. An initial IR-dose escalation study for the treatment of the right liver lobe in healthy mice demonstrated that single fractions of 20 Gy and higher resulted in substantial animal body weight loss and impairment of liver functional markers. Preliminary results in this murine CLM model revealed a partial radioprotective effect of ITPP in healthy liver. Targeted irradiation of the right liver lobe with single fractions of 10 and 15 Gy is effective in reducing the growth of metastatic lesions without causing radiation- induced toxicities. Conclusion Here we demonstrated that the combined treatment modality of ITPP and IR results in a supra-additive tumor growth delay, which is most probably linked to neoadjuvant tumor reoxygenation. Moreover, we demonstrate that the irradiation of murine CLMs is feasible, accurate and effective with a small-animal image-guided radiotherapy platform. OC-0055 Zebrafish model to study the use of nanoparticles as a radiosensitizer in low Z target beams M. Ha 1 , O. Piccolo 2 , N. Melong 3 , J. Lincoln 4 , D. Parsons 5 , A. Detappe 6 , O. Tillement 7 , R. Berbeco 8 , J. Berman 9 , J. Robar 10 1 Dalhousie University/Nova Scotia Health Authority, Radiation Oncology, Halifax, Canada; 2 Dalhousie University, Biology, Halifax, Canada; 3 IWK Health Centre/Dalhousie University, Pediatrics, Halifax, Canada; 4 Dalhousie University, Physics and Atmospheric Science, Halifax, Canada; 5 UT Southwestern Medical Centre, Radiation Oncolgy, Dallas, USA; 6 MIT, David H Koch Institute for Integrative Cancer Institute, Cambridge, USA; 7 Universite de Lyon, Institut Lumiere

Proffered Papers: RB 1: Pre-clinical models is the next step for radiotherapy

OC-0054 Tumor reoxygenation and image-guided SBRT for the treatment of murine colorectal liver

metastases M. Pruschy 1