A Comparative Study of Biological Effects of VHEE, Protons and other Radiotherapy Modalities Kristina Small University of Manchester, Christie NHS Foundation Trust, Cockcroft Institute

Background and Overview Project aim - to investigate the type and quantity of DNA damage caused due to irradiation of plasmid DNA by VHEE Brief introduction to Very High-Energy Electron therapy and its advantages Plasmid irradiation simulations using Geant4-DNA Experimental plans at VELA/CLARA Other activities during the year

VHEE – A Very Brief Overview The aim of any radiotherapy treatment is to deliver the maximum radiation dose to cancer cells while minimising the dose to healthy surrounding cells Currently, photon beams of energy up to 15 MV are used for the treatment of deep-seated tumours – however, high doses are delivered to surrounding healthy tissue Recent developments in the design of high-gradient accelerating cavities have allowed exploration of VHEE therapy (50 – 250 MeV)

VHEE – Potential Advantages Sufficient penetrative power to reach deep-seated tumours – 200 MeV corresponds to ~30 cm depth Marked insensitivity to inhomogeneities – unaffected by regions of changing density Improved dose delivery and organ-at-risk sparing compared with conventional photon therapy FLASH therapy – rapid delivery allows very high dose rates (> 40 Gy)

Plasmid Irradiation Simulation Plasmids are small, circular DNA structures distinct from chromosomal DNA. They have the advantage of being unable to repair after irradiation, allowing pure damage data to be measured Geant4-DNA, a Monte Carlo particle tracking code, is used to simulate early biological damage at the cellular and molecular level, specifically single- and double-strand breaks Simulation aims – firstly reproduce proton irradiation results produced by the PRECISE group Secondly, adapt the code to allow electron simulations and repeat simulations with VHEE for comparison

Plasmid Irradiation Experiments The VHEE plasmid simulations will form the basis of an experiment anticipated at the VELA/CLARA facility during the second quarter of 2018 Experiment aim – to quantify and compare the yield of single- and double-strand breaks resulting from irradiation of plasmid DNA by 10 – 50 MeV electrons over a range of doses up to 2000 Gy to previous proton data Dry and wet samples will be irradiated to measure the contribution of direct and indirect effects to the total damage

Plasmid Irradiation Experiments After irradiation, the plasmids will be analysed using a technique called Agarose Gel Electrophoresis to measure the relative amounts of super-coiled, open-circle and linear forms The relative amounts of the three plasmid forms will be fitted to Cowan’s 1987 model for calculation of SSB and DSB yields DNA molecules can be made to move through an agarose gel using an electric field Larger molecules move through the gel more slowly than smaller molecules, with the differently-sized molecules forming distinct bands on the gel

Conferences, Schools and Outreach March 2017 – Multi-Scale Monte-Carlo Modelling for Radiotherapy Sandpit (Manchester) March 2017 – Sharing the Vision for World-Class Radiotherapy Symposium (Manchester) June 2017 – Optimising Medical Accelerators School (Pavia, Italy) July 2017 – Very High Energy Electron Therapy: Medical and Accelerator Physics Aspects towards Machine Realisation (Daresbury). Poster presentation July 2017 – Volunteering with Erasmus summer school – ‘Diversity in the Culture of Physics’ November 2017 – Cockcroft Postgraduate Conference (1st place)

References Vysin, L et al., Proton-induced direct and indirect damage of plasmid DNA, 2015, Radiat. Environ. Biophys. 54: 343 – 352 Leloup, C et al., Evaluation of lesion clustering in irradiated plasmid DNA, 2005, Int. J. Radiat. Biol. 81: 41 – 54 Bazalova-Carter, M. et al. Treatment planning for radiotherapy with very high-energy electron beams and comparison of VHEE and VMAT plans. Med. Phys. 42, 2615–2625 (2015) Khan, V, ‘A Damped and Detuned Accelerating Structure for the Main Linacs of the Compact Linear Collider,’ University of Manchester, 2011 DesRosiers, C et al., ‘150-250 MeV electron beams in radiation therapy,’ Phys. Med. Biol. 45, 1781–1805 (2000)

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