Last update on June 2015
BioQuaRT (Biologically weighted quantities in radiotherapy) is a three-year-long European project launched in June 2012 that brings together seven partners. Its purpose is to gain additional knowledge regarding the dosimetry of ionizing radiation used in the medical field in order to potentially reconsider the concept of absorbed dose. The European Metrology Research Program provided 44% of the funding. Its aims are aligned with those of the IRSN (Institute for Radiological Protection and Nuclear Safety) ROSIRIS program launched in 2009.
Background and objectives
More than 50% of all cancer patients currently receive radiation therapy. While this treatment is effective, it can sometimes cause damage to healthy tissue. Good radiotherapy practice includes optimizing the dose delivered to the tumor in order to achieve the best possible therapeutic efficacy while minimizing the dose delivered to surrounding healthy tissue. Many technological advances can improve ballistics, including the use of ions.
The growing use of hadron therapy (radiotherapy using beams of protons or ions) in the treatment of cancer entails the need to establish new and more specific dosimetry concepts. Indeed, the biological effects of this type of radiation therapy on healthy tissue are poorly understood and differ from those of classical and stereotactic radiotherapy (which relies on the use of photon beams).
The primary objective of the BioQuaRT project is to define and quantify the link between energy deposits within cells caused by radiation particles and their subcellular effects (DNA double-strand breaks in particular). The project focuses on the development of simulation and measurement techniques for studying the topology of these deposits by determining the track structure1 of ionizing particles at scales ranging from 2 nm (diameter of the DNA double helix) to 10 microns (typical diameter of a cell nucleus). It thus aims to develop micro- and nanodosimeters whose sensitivity scale is suitable for the direct measurement of energy transfer for different particles at these scales.
The BioQuaRT program is structured into five work packages (WPs): four experimental WPs, all of which revolve all around a fifth WP focused on the development of a multiscale simulation of ionizing particle tracks and the following interactions:
- WP 1/Micro-Dosimetry (coordinated by NPL, UK)
It aims to develop microcalorimeter prototypes for the direct measurement of the energy deposited by ions at the cell nucleus scale, and with greater precision than existing microdosimeters (gas).
- WP 2/Nanodosimetry (coordinated by PTB, Germany)
This partnership makes use of the three nanodosimeters currently available in Europe: the Ion Counter (PTB, Germany), the Jet Counter (NCBJ, Poland) and StarTrack (LNL, Italy). These nanodosimeters measure the number of ionizations that occur in a nanosized "water equivalent" volume (different for each of the detectors and gases used). These measurements are compared to the results of the simulations and used to quantify direct damage to DNA. In addition, a device for measuring micro- and nanodosimetric parameters in coincidence must be built to achieve the first multiscale measurement (cell nucleus/DNA) of energy deposits.
- WP 3/Indirect Effects (coordinated by NPL, United Kingdom)
This package focuses on the experimental assessment of the indirect effects of ionizing radiation using probes that quantify and observe (2D and 3D) the reactive oxygen species (ROS) created by the radiolysis of water due to ionizing radiation that are characteristic of radiation-induced oxidative stress in cells.
- WP 4/ Radiobiology (coordinated by ENEA [Italian national agency for new technologies, energy and sustainable economic development], and contribution of the IRSN)
WP 4 focuses on observing the biological effects caused by ionizing radiation, such as DNA damage, and involves the study of several types of ion beams. The biological data collected will be used to validate the multiscale model developed in the context of WP 5. The IRSN endeavors to observe the early effects of ionizing radiation (signaling of DNA damage in the minutes following irradiation), while the ENEA and IST/ITN focus on its late effects (quantification of chromosomal aberrations).
- WP 5/ Multiscale model (coordinated by the IRSN)
This work package consists of developing a multiscale simulation model that brings together the properties of energy deposits at the nano- and micrometer scale on the basis of the GEANT4 code (Monte Carlo); the model will then be validated by comparing the simulations to all the biological data collected in the context of WP 4. This model also includes data gathered in WP 3 on the quantification of ROS.
Results of the IRSN and the project, outlook
The IRSN contributed to WP 4 (radiobiology) and WP 5 (multiscale simulation).
The "radiobiology" WP aimed to determine the likelihood of cell DNA damage (double strand breaks) according to the characteristics of the ionizing particle (type and energy). Experiments were conducted on a high-resolution single-ion microbeam (PTB, Germany) and human umbilical vein endothelial cells (HUVECs) and Chinese hamster ovary (CHO) cells were used. The relocation of DNA damage signaling proteins (γH2AX and 53BP1) was observed and quantified by immunofluorescence in the minutes that followed irradiation. The likelihood of DNA damage was thus determined based on the characteristics of the particle beam.
Multiscale simulation WP
The multiscale simulation WP focused on developing models representing the direct and indirect effects of charged particles (ions and electrons) on DNA molecules (sugar, phosphate...). This simulation makes it possible to calculate the location of energy deposits and thus to deduce the number of DNA breaks. To this end, the GEANT4 code (its Geant4-DNA extension in particular) was used as a basis for a modeling approach integrating new probabilities of physical interaction with DNA molecules. During simulation, if the charged particle interacts with the sugar-phosphate backbone in each strand, said interaction can induce DNA breakage (direct effect).
The geometry of the target molecule (DNA) was also built based on a specific model established by the IRSN. This was specifically necessary for simulating chemical interactions between the radicals generated by irradiation of the water molecule surrounding the DNA and the DNA itself. Indeed, these chemical reactions may also be the cause of DNA breaks (indirect effect).
Using the GEANT4-DNA code, the IRSN explicitly developed the interaction of OH radical with the sugar-phosphate backbone of DNA. The results obtained from the Monte Carlo simulation were then analyzed using "clustering" software to determine the position of double-strand DNA breaks as a according to the incident particle and its energy. In fine, these calculations can be compared to the biological data obtained in WP 4 and WP 3 in order to validate the models developed.
In March 2014, approximately 122,000 patients were treated across the 55 proton therapy and ion beam therapy centers distributed all over the world. The number of such facilities is set to double over the next few years. The development of dosimetric concepts based on measurable quantities related to the track structure of ionizing particles could thus have significant implications for the radiation oncology community. The BioQuaRT project has already given rise to 30 international scientific publications and more than a hundred communications since 2012.
1. Structure of a particle track: path and interactions (i.e. energy deposition) of each particle within the target.