Mapping the Relative Biological Effectiveness of Proton, Helium and Carbon Ions with High-Throughput Techniques.

Lawrence Bronk,Duo Ma,Amir Abdollahi,Radhe Mohan,Kevin Tran,Clifford Stephan,Joycelyn Yiu,Jürgen Debus,Oliver Jäkel,Benjamin Kroger,David R Grosshans,Xiaochun Wang,Darshana Patel,Uwe Titt,Fada Guan

doi:10.3390/cancers12123658

Abstract

Simple SummaryAlthough particle therapy using protons and heavier ions has many inherent advantages when compared to x-rays for cancer treatment, numerous unknowns still exist in the radiobiology of particle therapy. Informative high-accuracy biological effects data are lacking and difficult to obtain. This study aimed to provide a novel high-throughput experimental method to more efficiently obtain large amounts of biophysical data of particle therapy and to correlate the biological responses with the physical characteristics of particle beams.Large amounts of high quality biophysical data are needed to improve current biological effects models but such data are lacking and difficult to obtain. The present study aimed to more efficiently measure the spatial distribution of relative biological effectiveness (RBE) of charged particle beams using a novel high-accuracy and high-throughput experimental platform. Clonogenic survival was selected as the biological endpoint for two lung cancer cell lines, H460 and H1437, irradiated with protons, carbon, and helium ions. Ion-specific multi-step microplate holders were fabricated such that each column of a 96-well microplate is spatially situated at a different location along a particle beam path. Dose, dose-averaged linear energy transfer (LETd), and dose-mean lineal energy (yd) were calculated using an experimentally validated Geant4-based Monte Carlo system. Cells were irradiated at the Heidelberg Ion Beam Therapy Center (HIT). The experimental results showed that the clonogenic survival curves of all tested ions were yd-dependent. Both helium and carbon ions achieved maximum RBEs within specific yd ranges before biological efficacy declined, indicating an overkill effect. For protons, no overkill was observed, but RBE increased distal to the Bragg peak. Measured RBE profiles strongly depend on the physical characteristics such as yd and are ion specific.

Highlights

In recent years, interest in using heavier charged particles, i.e., protons and carbon ions, in cancer treatment has increased markedly
Our previous work demonstrated agreement of the LETd -dependent proton relative biological effectiveness (RBE) trend of H460 cells measured using the high-throughput clonogenic assay between the two institutions [27]
The lethal α- and sub-lethal β- components from the linear quadratic (LQ) model fit trended increasing with LETd (Figure 1C; Table S1)

Summary

Introduction

Interest in using heavier charged particles, i.e., protons and carbon ions, in cancer treatment has increased markedly. Harnessing the differential biological effects of a given therapeutic ion beam by placing the regions with low biological effect in normal tissues and those with increased efficacy in the tumor volume are the core tenets driving biologically optimized particle therapy. This requires understanding the complex spatial distribution of biological effects of ions, i.e., as a function of particle type and energy, beam characteristics, dose, tissue or cell type, and biological endpoint [9,10,11,12,13]. Such spatial mapping remains limited because of the low efficiency of traditional experimental techniques

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