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Spatial fractionation of the dose in proton therapy: a novel therapeutic approach

Periodic Reporting for period 2 - PROTONMBRT (Spatial fractionation of the dose in proton therapy: a novel therapeutic approach)

Reporting period: 2021-04-01 to 2022-09-30

Radiotherapy (RT) is one of the most frequently used methods for cancer treatment (above 50% of patients will receive RT). Despite remarkable advancements, the dose tolerances of normal tissues continue to be the main limitation in RT. Finding novel approaches that allow increasing normal tissue resistance is of utmost importance. This would make it possible to escalate tumour dose, resulting in an improvement in cure rate. With this aim, we propose a new approach, called proton minibeam radiation therapy (PROTONMBRT), which combines the prominent advantages of protons for RT and the remarkable tissue preservation provided by the use of submillimetric field sizes and a spatial fractionation of the dose, as in minibeam radiation therapy (MBRT). The main objectives of this project are to explore the gain of therapeutic index for radioresistant tumours, to disentangle the biological mechanisms involved and to evaluate the clinical potential of this novel approach. For this purpose, a method for minibeam generation adequate for patient treatments and a complete set of dosimetric tools will be developed. Then, tumour control effectiveness will be evaluated, and the possible biological mechanisms involved both in tumour and normal tissue responses will be disentangled. The gain in normal tissue recovery can foster one of the main applications of proton therapy, paediatric oncology, as well as open the door to an effective treatment of very radioresistant tumours, such as high-grade gliomas, which are currently mostly treated palliatively.
One of the main challenges of this novel technique, proton minibeam radiation therapy, was to how generate narrow proton beams at clinical centres (which are designed to produce the opposite, i.e. broad beams).
Two different new and optimised methods for proton minibeam generation at a clinical centre have been conceived. As a result, two patent applications have been submitted and 4 papers have been published.
Suitable dosimetry protocols for the narrow beams employed in pMBRT have been developped. Critical radioprotection aspects have been assessed, not finding any safety issues in pMBRT.
A first evaluation of treatments' plans for potential patients has been performed, showing that pMBRT may offer a satisfactory tumor dose coverage while normal tissues will benefit from the strong modulation of the dose.
A remarkable reduction of neurotoxicity after pMBRT has been demonstrated in small animal experiments. An equivalent or even superior tumor control as compared with standard radiotherapy was also achieved in different high-grade glioma models.
Thus far, our work has resulted in 15 papers published, several under preparation, two patent applications, more than 15 invited presentations in international congresses, and several other oral and poster presentations.
In this first half of the project we have conceived two different new and optimised methods for proton minibeam generation at clinical centres. Two patent applications have been submitted, and some industrial collaborations have been started.
Adequate dosimetry protocols for preclinical studies in pMBRT have been developped. We have demonstrated that pMBRT reduces neurotoxicity (in terms of cognitive, emotional and motor processes).
The first temporal and spatial fractionated pMBRT irradiations of glioma-bearing rats led to 80 % long-term survivals free of tumors, which is the best result ever obtained with radiotherapy alone (in this tumor type).
In the second half of the project, we expect to deepen our comprehension of the biological mechanisms of the remarkable normal tissue sparing and tumor control of pMBRT.
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