Novel image reconstruction techniques with application to proton radiotherapy for optimisation of cancer treatment

One in two people will develop cancer, and cancer is the cause of approximately one third of all UK deaths. Radiotherapy accounts for >40% of curative treatments, owing its effectiveness in the ability to accurately target tumours. Proton Beam Therapy (PBT) is rapidly gaining momentum compared to x-ray/electron beams with more than 63 operating sites and 40 sites under construction worldwide. Protons have similar relative biological effectiveness (RBE) to photons, but an excellent depth-dose distribution profile that allows better conformation of dose distribution to target compared to x-rays or electrons, thereby reducing the integral dose to the body and avoiding to dose normal tissue structures near the tumour. This is crucial when treating growing children, to avoid side effects such as developmental delays, hormone deficiencies, effects on bone and muscle tissue, and hearing loss or damage to salivary glands. The two main methods to deliver proton beams is via passive spreading and spot scanning PBT. Spot scanning PBT is a new therapy that penetrates deeper and produces fewer neutrons than passive spreading, further decreasing the integral dose and the risk of secondary cancer, but is more sensitive to spatial errors increasing the risk of delivering the dose in the wrong place. Spot scanning PBT can deliver treatments in sub-mm accuracy, but because of imaging limitations prior to treatment, upon which the treatment is planned it currently cannot achieve more than 7 mm accuracy. To maximise the potential of PBT it is crucial to accurately know the dose distribution and be able to shape and control it, making imaging the number one challenge for accurate treatment planning. Based on the reconstructed images, proton stopping power maps are calculated, which inform us about the dose distribution. Due to the proton Bragg peak characteristic a miscalculation in the proton stopping power map (distance from the 90% to the 10% dose level is only a few mm) can result in the proton beam missing its target and damaging healthy tissue, while the tumour receives much lower dose. This work will initially quantify proton stopping power maps directly from proton CT (pCT), aiming to reduce range uncertainties and enhance PBT accuracy. pCT measures the energy loss for protons traveling along tracks allowing the estimation of the integrated relative electron density with respect to a reference medium along the proton path. Proton stopping power maps can be estimated directly by inverting the path integral. Current reconstruction algorithms, such as the filter back-projection approaches, falsely assume Gaussian energy straggling distribution, and do not account for multiple Coulomb scatter (MCS). Reconstructed pCT images become blurred by MCS, which results in a resolution of around 3-5 mm and the energy spread distributions in fact resemble asymmetric Gaussian functions due to electronic energy-loss straggling and MCS. The proposed pCT reconstruction will account for non-Gaussian energy loss distributions, and iteratively correct for MCS to improve the spatial resolution and accuracy of proton stopping power maps. With expected anatomical changes of both tumour and normal tissue during a typical 5-7 week course of radiation, relying solely on a pCT acquired before therapy will lead to under dosing of the tumour and/or unnecessary exposure of organs at risk to higher doses. This proposal addresses ways to fuse information from pCT (acquired before treatment) in the reconstruction of limited number of projections during spot scanning PBT, and update the proton stopping power map during the treatment. The proposed methods will make on-treatment imaging feasible, allowing for significant improvement in treatment planning.

One in two people will develop cancer, and cancer is the cause of approximately one third of all UK deaths. Radiotherapy accounts for >40% of curative treatments, owing its effectiveness in the ability to accurately target tumours. Proton beams just as x-rays are used to treat both benign and malignant tumours, in a similar way. There is no significant difference in the biological effects of protons versus x-rays. However, protons deliver a dose of radiation in a much more confined way to the tumour tissue than photons. Proton beam therapy's (PBT) advantage is its superior dose distribution compared to x-rays, but it is also its most challenging aspect. Protons release most of their energy within the tumour region and, unlike photons, deliver only a minimal dose beyond the tumour boundaries reducing the possibility of secondary cancer. This is especially important when treating paediatric cancer, because protons help reduce radiation to growing and developing tissues. The proposed research will make on-treatment PBT imaging feasible, allowing for significant improvement in treatment planning. Accurate treatment planning is crucial in paediatric cancer and areas like the neck because (i) of the close proximity of tumours to multiple critical organs and (ii) the anatomy is likely to change between the time of imaging and therapy and during therapy.

Currently there are 63 operational PBT centres worldwide with a further 40 in planning or under construction, with an estimated doubling of centres every four years. These figures represent ~300 treatment rooms. Within the UK alone, two NHS centres and 7 private ones are opening over the next few years. The NHS provision is based on 1% of radiotherapy patients benefit from PBT (~1,500 patients/year); however many experts suggest a figure of ~10% (which would make ~15,000 patients/year).

The immediate beneficiaries of this proposal will be the members of the Proton Radiotherapy Verification and Dosimetry Applications (PRaVDA) consortium, and the open source software for image reconstruction (STIR) community where the proposed methods will be developed. PRaVDA is a consortium of 6 universities (Lincoln, Liverpool, Birmingham, Surrey, Warwick, Cape Town), 4 NHS Trusts, Karolinska University Hospital, Sweden, and iThemba LABS, South Africa. PRaVDA is a world-leading consortium in the development of a proton CT based solely on solid-state devices and was represented in the IET's "One Hundred Objects that Changed the World" exhibition at Savoy Place. CVSSP is ideally placed as the only image reconstruction centre within the consortium, responsible to solve the reconstruction problem posed from the PRaVDA prototype proton CT and the methods developed during this grant will immediately benefit the consortium. This collaboration will provide the platform to both deploy the technology for evaluation in novel proton CT systems and enable technology transfer within the leading research sites in PBT. Code and toolboxes will also be made public via STIR. Currently STIR supports toolboxes for PET/SPECT tomography, this grant will have a significant impact on the STIR community providing additional toolboxes for proton CT and PBT imaging. Initial links have already been established with the PBT centre at UCLH, to translate the PBT imaging methods developed in this proposal to the clinic.
Broader impact: Although this grant aims to improve proton imaging/radiotherapy, the proposed methodologies would also benefit other areas of research that involve proton beams such as imaging of biological structures, and chemical composition of materials.