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Contrast Agents for Protontherapy PET Range Monitoring

Periodic Reporting for period 1 - CAPPERAM (Contrast Agents for Protontherapy PET Range Monitoring)

Reporting period: 2018-12-01 to 2020-11-30

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. 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.

1) Develop a calculation tool that can predict the effect of contrast agents during proton irradiation and identify relevant potential contrast agents.
2) Produce proof-of-principle data using phantoms or animal models to validate the technique.

The global aim is to reduce uncertainty margins in proton therapy, increasing its therapeutic window and reducing side effects.
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, see Figure 1). 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 (Figure 2). 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 (see Figure 3), which allowed a submillimetric localization of the irradiated volume.

Main scientific results:
- W-18 was identified as most promising contrast agent for proton radiotherapy thanks to its simplicity of use, high-concentrations achievable in tissue and range neutrality. Other candidates, such as Zn nanoparticles or iodine, remain under study.
- A dose-activity calculation algorithm was implemented and validated against experimental measurements (España et al 2020, Rad.Phys.Chem in press).
- Cross-section measurements for Zn and I targets were performed, including the first reported set of experimental data for the 127I(p,n)127mXe reaction (Espinosa et al 2020, Rad.Phys.Chem under review).
- As a final proof-of-concept testing all stages of the project, 18-W was used to image dose-maps delivered to tumors grown at the CAM of chick embryos, using a preclinical PET scanner (España et al 2020, Med. Phys, under review).
- Reported advances in electronics (Sánchez-Tembleque et al 2019) and collaboration in joint projects has allowed for measurements at the Quironsalud proton therapy center (Mazal 2020, Front. Oncol).
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 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.

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 ( In the framework of this project, the radiopharmaceutical group at CIEMAT ( has started investigation on takeup of Zn nanoparticles, which will continue in the future. Also, collaborations with the Center for Microanalysis of Materials ( and the Quironsalud proton therapy center ( 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 ( 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:
An improvement of the accuracy of proton therapy could help making it more widely available for the general public. Also, the proposed enhancements could lead to a potential reduction of acute and long-term side effects of protontherapy treatments.
The dissemination activities for the general public have contributed to raising general knowledge on an important topic such as radiation effects and radiotherapy as a tool to fight cancer.
The established consortia will continue to carry out ground-breaking research in the field of cancer radiotherapy.
F3: Dose deposition (left) and PET/CT images (right) of three of the irradiated eggs.
F1: TOPAS-simulated (left) and acquired (right) PET activity image, for a 60-minute frame.
F2: Process of inoculating W18 and performing proof-of-principle study.