Periodic Reporting for period 1 - CAPPERAM (Contrast Agents for Protontherapy PET Range Monitoring)
Reporting period: 2018-12-01 to 2020-11-30
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.
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 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:
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.