The radiotherapy workflow
Radiotherapy is typically fractionated over several weeks, with the patient receiving every weekday a fraction of the total prescribed dose. This leaves time for the normal tissues to recover and minimises the acute radiation effects.
The treatment planning is performed once per patient, before the start of his treatment, and consists of optimising the beam delivery parameters in order to reach the prescribed dose at the target volume (i.e., the tumour tissue) while maintaining the dose to organ at risks and healthy tissue below defined limits.
A radiotherapy treatment workflow consists first in installing the patient in his treatment position, which should be repeatable from one fraction to the other. The positioning is made thanks to lasers and can be refined with anatomical x-ray images. The treatment plan is then delivered.
Uncertainties in dose delivery may arise from various sources, such as inaccuracies in patient positioning (alignment, patient motion during delivery) or drift in machine output. Additionally, the patient anatomy generally changes over the course of the treatment, which can lead to reduced tumour conformity.
Quality assurance (QA) aims at verifying that the prescribed and planned dose are delivered at the intended location, using tissue-mimicking phantoms and radiation dosimeters. However, there is always a trade-off between the amount of time that can be allocated to QA and the coverage of those tests. The delivered dose at the level of the patient skin is also generally verified during delivery of the first fraction. However, currently, we are not able to quantify the dose actually delivered within the patient’s body, at the level of the tumour or the organs at risk. As patient treatments are becoming increasingly complex and personalised, routine QA and point measurements at the skin level will no longer be sufficient to warrant patient safety and ensure the accuracy of the treatment.
Ultrasound Contrast Agents
Ultrasound has been routinely used in hospitals as a diagnostic tool for more than 50 years. Ultrasound anatomical images are obtained by analysing reflected signals coming from boundaries of tissues having different acoustic properties. Blood poorly reflects ultrasound and therefore microbubbles have been introduced to act as ultrasound contrast agents (UCAs) to improve images of the vasculature. Microbubbles are micron-sized gas cavities encapsulated by a shell made of lipids, polymers or proteins. When exposed to ultrasound, microbubbles undergo large volumetric oscillations and produce acoustic emissions that can be detected by an ultrasound probe. Their acoustic response depends on a variety of factors, amongst which their physico-chemical and structural properties. Additionally, the shell of the microbubbles can be functionalised and targeted to specific types of cells in the body.
Our in-situ radiation dosimeter is based on functionalised, radiosensitive ultrasound contrast agents. A direct, on-line assessment of the radiation dose delivered to the patient during the treatment delivery will be obtained through the following workflow:
Microbubbles are injected systemically to the patient a few minutes before the radiotherapy treatment. The targeted contrast agents will circulate in the whole body and accumulate at the tumour location, thanks to the binding of ligands incorporated onto the microbubble shell with specific cell receptors.
Prior to the radiotherapy treatment, a reference ultrasound image is obtained. This reference measurement gives the acoustic signature of the microbubble population at the tumour site.
Then, the radiation therapy treatment is delivered. It is hypothesised that ionising radiation can modify the physico-chemical properties of the microbubbles, and that it will in turn induce a modification of the microbubble acoustic signature.
After (or during) the treatment, a second ultrasonic measurement is made. Comparison between the microbubble acoustic signatures for the reference measurement and the dosimetric measurement enables to calculate a 3D dose distribution map.
Thanks to the knowledge of the dose distribution in (and around) the tumour, clinicians and medical physicists are able to verify the success of treatment delivery and detect failures in machine output, hereby preventing the spread of radiotherapy accidents. Additionally, they can assess changes in the patient anatomy that may require an adjustment of the treatment plan, opening the door to advanced treatment techniques such as adaptive radiotherapy. An UCA-based dosimeter has the potential to form the basis for real time dose tracking, that would be the ideal input for advanced automated control systems capable of adapting the treatment process in view of maximising the compliance with the prescribed dose distribution.
The above concept has already been tested and validated in vitro with commercial UCAs. The attenuation of several microbubble populations (Targestar, Sonovue, MicroMarker) has been evaluated before and after exposure to a 6 MV photon beam.
The graph below shows the maximal attenuation with respect to the delivered radiation dose for two vials of Targestar-P. The grey area indicates the range of ultrasonic measurements on reference samples without radiation. This shows that ionising radiation can impact the microbubble properties and that this change is detectable in the microbubbles acoustic signatures.