ESTRO 36 Abstract Book

S311 ESTRO 36 _______________________________________________________________________________________________

In vitro , SN36506 preferentially kills tumor cells in hy poxic conditions and reduces clonogenic cell survival of hypoxic spheroids only. In vivo, SN36506 sterilizes radiation resistant hypoxic tumor cells, and strongly inhibits tumor growth. As such, SN36506 is a promising new HAP with potentially favorable properties for clinical use. Further studies to determine the antitumor effects of SN36506 as a monotherapy and in combination with RT in several preclinical tumor models are ongoing.

countries now have paedidatric stratified medicine programmes underway or in development, and the first multi-arm, multi-Pharma company European paediatric basket trial – e-SMART – is due to open for relapsed and refractory tumours. At a strategic level, consultation is underway for the EU ‘Paediatric Regulation’ which it is hoped will further increase access of children to novel therapies by removing the facility for Pharma companies to apply for waivers for paediatric testing. In an era of molecularly driven therapy, such waivers have no logical basis in the majority of cases. OC-0591 Hypoxic cell killing by SN36506, a novel hypoxia-activated prodrug R. Niemans 1 , A. Yaromina 1 , J. Theys 1 , A. Ashoorzadeh 2 , R. Anderson 2 , M. Bull 2 , C. Guise 2 , H.L. Hsu 2 , M. Abbattista 2 , A. Mowday 2 , A.V. Patterson 2 , J.B. Smaill 2 , L. Dubois 1 , P. Lambin 1 1 Maastricht Radiation Oncology MAASTRO GROW - School for Oncology and Developmental Biology- University Maastricht, Department of Radiotherapy, Maastricht, The Netherlands 2 University of Auckland, Auckland Cancer Society Research Centre, Auckland, New Zealand Purpose or Objective Hypoxia is a common feature of solid tumors. Conventional treatments such as chemo- and radiotherapy (RT) are less effective against hypoxic tumor cells. Hypoxia-activated prodrugs (HAPs) are specifically activated under hypoxic conditions to directly target these as well as adjacent more oxygenated tumor cells via their bystander effect. SN36506 is a newly developed nitroaromatic HAP with highly favorable properties: 1) activation under hypoxia, 2) high bystander effect, 3) excellent aqueous solubility, 4) murine oral bioavailability and 5) no off-mechanism activation by human aerobic reductases. Here we tested the cytotoxic effects of SN36506 in vitro and in vivo . Material and Methods IC 50 viability ratios were assessed in 2D cell culture exposed to normoxic or anoxic (≤0.02% O 2 ) conditions in a panel of human tumor cell lines. H460 lung tumor multicellular layers (MCLs) were incubated with SN36506 under aerobic (5% CO 2 , 95% O 2 ) or anoxic (5% CO 2 , 95% N 2 ) conditions and plated for clonogenic cell survival (CCS). In addition, H460 spheroids were incubated with SN36506, after which single cell suspensions were made and cells were plated for CCS. Mice bearing H460 xenografts received a single i.p. dose of SN36506 (781 mg/kg) after irradiation (10 Gy) of tumors. 18 h later tumors were excised, single cell suspensions were prepared and plated for CCS. Mice bearing xenografts of a range of tumor cell lines received one i.p. dose of SN36506 (800 mg/kg) per day on 5 consecutive days (QD5). Treatment started when tumors reached a volume of approximately 200 mm 3 , and tumor volumes were followed-up after treatment. Results IC 50 were lower in anoxia than normoxia by factors of 20.17 (SiHa), 55.11 (C33A), >7.84 (HCT116), >3.66 (DLD-1), >12.9 (MDA-MB-468), >2.67 (H1299) and >6.21 (H460). In a H460 MCL clonogenic assay, 100 µM SN36506 caused 99% cell kill under anoxia but exhibited no aerobic cell kill. SN36506 caused a concentration-dependent decrease in survival of clonogens derived from hypoxic spheroids but had no effect on clonogenic cells from non-hypoxic spheroids, indicating hypoxia-specific cell kill. A single dose of SN36506 significantly reduced clonogenic cell survival when combined with RT in an in vivo excision assay (log cell kill 2.35 relative to control). Furthermore, in vivo 800 mg/kg QD5 of SN36506 caused xenograft growth inhibition of 99.6% (MDA-MB-468), 81% (A2780), 52% (H460) and 41% (SiHa). Conclusion

Symposium: Applications and challenges in dosimetry for MR-linacs

SP-0592 Reference dosimetry: getting the basics and calibration right S. Duane 1 National Physical Laboratory, Teddington, the United Kingdom

Abstract not received

SP-0593 Clinical commissioning of MR guided treatment systems O. Green 1 Sietman Cancer Center, Saint Louis, USA

Abstract not received

SP-0594 Pre-treatment phantom dosimetry: effects in different phantoms and detectors B. Van Asselen 1 , J.W.H. Wolthaus 1 , S.L. Hackett 1 , J.G.M. Kok 1 , S.J. Woodings 1 , B.W. Raaymakers 1 1 UMC Utrecht, Department of Radiation Oncology, Utrecht, The Netherlands The excellent visualization of soft-tissue with MRI can allow direct visualization of the tumor when applied during the delivery of radiotherapy. Several designs, which combine MRI with either an accelerator or Co-60, are being developed or in clinical use. At the UMC Utrecht a clinical prototype is installed which integrates a 1.5 T MRI scanner and a 7 MV linear accelerator. When the dose is delivered in presence of a magnetic field, the Lorenz force will change the trajectories of the high energy electrons generated by the megavoltage radiation. The effect on dose distribution depends on the magnetic field strength, its direction relative to the treatment field and the energy. In our MRI-linac design this results in a decreased build-up distance and a shifted penumbra. Changes can also be observed in the dose distribution near interfaces of two materials with different densities. Especially near tissue-air boundaries electrons can be curved back into the tissue (electron- return-effect). The influence of the magnetic field can also affect the reading of various detectors used for reference dosimetry, acceptance and commissioning, regular QA and patient QA. The change in reading of a detector depends on the field strength, orientation relative to the photon field and the magnetic field and to sources of air-layers between build-up material and detector. An important detector is the waterproof farmer type ionization chamber, which performance in a magnetic field has been investigated thoroughly in our department. Correction factors had been derived for the magnetic field in various geometries and orientations to obtain absolute dose measurements. The performance was characterized in water as well as solid water phantoms. Also the use of other detectors such as a diamond detector have been investigated for use in magnetic fields. To evaluate dose distributions of clinical plan delivery, patient specific quality assurance can be performed using various dedicated detectors, such as the Delta4 and