CAPPERAM: Contrast Agents for Protontherapy PET Range Monitoring

IP: Daniel Sánchez-Parcerisa
Sedecal Molecular Imaging + Universidad Complutense de Madrid

dsparcerisa [at] ucm.es

Project funded by the European Commission through the H2020-MSCA-IF-2017 call, grant agreement 793576. More info at the EU project website

Summary

Particle therapy is an innovative mode of external radiotherapy that utilizes the favourable ballistic properties of protons and carbon ions (vs. photons and electrons) to deliver more conformal dose distributions in the patients, maximizing doses to the target volumes whilst minimizing risks to surrounding healthy tissues. Particle therapy has treated over 200,000 patients worldwide (www.ptcog.ch) and the number of treatment rooms is growing exponentially. The key physical principle of particle therapy is that the beam range in the patient is highly dependent on the energy of the particles, as well as on the geometry traversed by them. Such a precise tool is therefore subject to uncertainties in predicting the stopping position of ions inside the patient’s body and therefore, to fully exploit these dosimetric advantages in clinical practice, it would be required to visualize the stopping position of ions in-vivo.

In radiation therapy, proton therapy has a more favourable dose distribution than conventional radiotherapy with photons and electrons. However, in order to fully exploit this dosimetric advantage, it would be required to verify the range of protons in the patient with mm accuracy. The most used strategy for in-vivo range verification in protontherapy relies on positron emission tomography (PET) activation. As they progress through the patient, proton beams undergo nuclear reactions that can produce radioactive isotopes, some of which are positron-emitters. This induced radioactivity can be detected in commercial or dedicated PET scanners and used to deduce the delivered dose distribution in the patient.

While a promising technique, two main challenges have so far limited its clinical implementation: first, the proton interaction cross sections of the elements making up the body (C, O, N, H) are relatively low, which causes the positron disintegration counts detected by the PET scanners to be about 1 or 2 orders of magnitude lower than the usual numbers in nuclear medicine. And second, the spatial and temporal distributions of PET emitters follow a very complex relation with the dose depositions which complicate the range verification process.

The CAPPERAM project aims at solving these two problems by administering contrast agents in patients prior to irradiation. Some elements, such as Zn, have a very high cross section for proton interaction peaking at very low proton energies, which would produce a very high concentration of PET emitters near the end of the proton range.

The main aims of the project are:

The success of the CAPPERAM project would pave the wave for a reduction of the uncertainty margins in proton therapy, increasing its therapeutic window and reducing side effects.

Main activities

The work established for CAPPERAM has been carried out in full, in the period of 01.12.2018 to 30.11.2020, by the researcher Daniel Sánchez Parcerisa in a joint effort between Sedecal Molecular Imaging (SMI) and the Nuclear Physics Group at Complutense University of Madrid (GFN-UCM).

The initial plan has been carried out with the following modifications:

Most of the work in the first stages of CAPPERAM was devoted to developing a calculation tool for activation of contrast agents. This was implemented using TOPAS Monte Carlo framework and a careful evaluation of existing proton-reaction cross sections. The calculation tool was validated against phantom measurements using water enriched with 18-O (18W) as a contrast agent. These measurements were carried out at the WPE center in Essen (España et al 2020a). Some of the cross-sections required for an accurate prediction of the induced activity were not readily available in the literature; therefore, with the help of colleagues at the Nuclear Physics Group at UCM, we implemented an online setup for measuring activation cross sections and used it at a number of experimental campaigns at CMAM (Espinosa et al, 2020) and WPE.

Finally, promising results using 18-W as contrast agent allowed us to perform an end-to-end proof-of-concept study using chick embryos as an animal model. In collaboration with colleagues at the Department of Biochemistry and Molecular Biology of the UCM, tumors grown at the chorioallantoic membrane (CAM) of chick embryos were infused with 18-W and irradiated with low-energy proton beams. Shortly after irradiation, dynamic PET images were acquired using a SuperArgus PET/CT scanner at Sedecal Molecular Imaging, which allowed a submillimetric localization of the irradiated volume.

The main results of the CAPPERAM project can be summarized as follows:

Results

The main result of the CAPPERAM project has been the proof-of-concept study using 18O-enriched water as a suitable contrast agent for in-vivo range verification in proton therapy evaluated in-vivo in a chicken embryo CAM tumor model of head and neck cancer. Results show 18F activation and retention within the tumor in the last millimeter of the proton range, which makes it ideal for direct proton range measurement using offline PET imaging. The longer half-life of 18F enables the possibility to record its signal on already available PET scanners more than 2 hours after irradiation to minimize the contribution from other isotopes with high production thresholds while a large fraction of the produced 18F remains entrapped within the tumor cells.

The observed results encourage us to proceed with further in-vivo experiments in larger animals and with clinically relevant proton beam energies to validate and assess the capabilities of 18O-enriched water as a suitable contrast agent for range verification in proton therapy. In order to achieve a high-enough 18O concentration in the irradiated volume, different routes of administration and irradiation protocols will be also studied.

The project activities have sparkled further collaboration with other groups. The biggest synergy has emerged with the PRONTO project, whose objectives are aligned with those of CAPPERAM (http://nuclear.fis.ucm.es/pronto-en/index.html). In the framework of this project, the radiopharmaceutical group at CIEMAT (http://rdgroups.ciemat.es/web/radiobiomed) has started investigation on takeup of Zn nanoparticles, which will continue in the future. Also, collaborations with the Center for Microanalysis of Materials (https://www.cmam.uam.es/en) and the Quironsalud proton therapy center (https://www.quironsalud.es/en/protonterapia), both located within the Madrid region, have been successful and planted a seed for further work. The experiments with preclinical models (such as chicken embryos) carried out in collaboration with colleagues at the Department of Biochemistry and Molecular Biology at UCM (https://www.ucm.es/bbm) have allowed us to initiate a consortium that will study proton radiobiology, in particular towards the study of FLASH dose rates and LET effects in proton radiotherapy.

The main socioeconomic and wider implications of the project results are as follows:

Scientific contributions

Articles in peer-reviewed journals

Invited talks delivered by principal investigator

Invited talks delivered by other members of the team, relevant to the CAPPERAM project

Posters at international conferences