Laser-driven beams for future medical applications

Cancer is one of the leading causes of death in developed countries and one-third of the population experiences it during their lifespan. Moreover, about half of all cancer patients undergo some form of radiotherapy. In recent years, proton-based radiotherapy has attracted growing interest and has become an increasingly common treatment modality. The exploitation of accelerated protons for cancer treatment is based on their superior ballistic properties compared to photons, which translates in advantages in terms of dose distribution to tumor and sparing of normal tissue. Clinical facilities employing charged-particle beams produced by synchrotron, cyclotron or LINAC accelerators have to face high installation (approximately 200M€ per center), management and running costs besides the large spaces required to install such equipment. These represent serious limiting factors. In fact, worldwide the existing hadrontherapy centers are very few (about 40) compared to the demand. The need for cost and size reduction has stimulated research activities spanning across physics, biology and medicine to develop novel, more cost-effective ways of cancer treatment pointing to compact, single-room accelerators as a possible alternative. Optical ion acceleration based on laser-plasma interaction has become a popular topic for multidisciplinary applications and opened new scenarios in the ion therapy framework, representing a possible future alternative to classic accelerators reducing costs and operational complexity. Particle acceleration from laser-matter interaction is an emerging technique employing ultra-short (from fs to ps) and ultra-intense (≥ 10^19 W/cm^2) power lasers to produce particle bursts of ultra-high dose-rates (≥ 10^9 Gy/s), which are orders of magnitude larger than the ones used in conventional therapy (1-10 Gy/min). Up to now, the highest energies laser-driven ion beams have been obtained exploiting the TNSA (Target Normal Sheath Acceleration) regime identified as the appropriate mechanism to produce, in a near future, energies useful for medical applications, i.e. in the order of 250 MeV. Clinically amenable laser-driven proton beams require specific constraints to be met, such as beam reproducibility, homogeneity and stability. Therefore, there is a significant technological effort to achieve a satisfactory level of the beam parameters as well as understand the biological consequences that a regime much different from the conventional one can have. In this thesis, proof-of-principle experiments are described that aimed at optimizing the control of such peculiar beams from the dosimetric point of view (TARANIS laser facility, Belfast, UK) and at collecting preliminary data on their radiobiological effectiveness (LULI laser facility, Paris, France). The latter is a mandatory task to validate any possible future use in cancer therapy of laser-driven protons. The results obtained are promising and, if corroborated by future experiments, may represent the first step towards a much hoped-for clinical feasibility. The work has been carried out in the framework of the EU funded project ELIMED and the Italian joint project PLASMAMED (funded by the Italian National Institute for Nuclear Physics, INFN)

Development of a low-energy particle irradiation facility for the study of the biological effectiveness of the ion track end

Uncertainties surround the radiobiological consequences of exposure to charged particles, despite the increasing use of accelerated ion beams for cancer treatment (hadrontherapy). In particular, little is known about the long-term effects on normal tissue at the beam entrance or in the distal part of the Spread-Out Bragg Peak (SOBP). Moreover, although the relative biological effectiveness (RBE) of particle radiation has been traditionally related to the radiation linear energy transfer (LET), it has become increasingly evident that radiation-induced cell death, as well as long term radiation effects, is not adequately described by this parameter. Hence, exploring the effectiveness of various ion beams at or around the Bragg peak of monoenergetic ion beams can prove useful to gain insights into the role played by parameters other than the particle LET in determining the outcome of particle radiation exposures. In this context, the upgrade of the Tandem irradiation facility at Naples University here described, has allowed us to perform a series of preliminary radiobiological measurements using proton and carbon ion beams. The facility is currently used to irradiate normal and cancer cell lines with ion beams such as oxygen and fluorine

Relative biological effectiveness variation along monoenergetic and modulated Bragg peaks of a 62-MeV therapeutic proton beam: A preclinical assessment

The biological optimization of proton therapy can be achieved only through a detailed evaluation of relative biological effectiveness (RBE) variations along the full range of the Bragg curve. The clinically used RBE value of 1.1 represents a broad average, which disregards the steep rise of linear energy transfer (LET) at the distal end of the spread-out Bragg peak (SOBP). With particular attention to the key endpoint of cell survival, our work presents a comparative investigation of cell killing RBE variations along monoenergetic (pristine) and modulated (SOBP) beams using human normal and radioresistant cells with the aim to investigate the RBE dependence on LET and intrinsic radiosensitvity. Methods and Materials Human fibroblasts (AG01522) and glioma (U87) cells were irradiated at 6 depth positions along pristine and modulated 62-MeV proton beams at the INFN-LNS (Catania, Italy). Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and the local effect model (LEM). Results We observed significant cell killing RBE variations along the proton beam path, particularly in the distal region showing strong dose dependence. Experimental RBE values were in excellent agreement with the LEM predicted values, indicating dose-averaged LET as a suitable predictor of proton biological effectiveness. Data were also used to validate a parameterized RBE model. Conclusions The predicted biological dose delivered to a tumor region, based on the variable RBE inferred from the data, varies significantly with respect to the clinically used constant RBE of 1.1. The significant RBE increase at the distal end suggests also a potential to enhance optimization of treatment modalities such as LET painting of hypoxic tumors. The study highlights the limitation of adoption of a constant RBE for proton therapy and suggests approaches for fast implementation of RBE models in treatment planning

In Vitro sub-lethal and non-targeted effects on normal human cells along the Bragg curve for different ion beams.

Linear Energy Transfer (LET) is the main physical parameter to compare charged particles to photons and predict their higher effectiveness. Damage complexity governs cellular radioresponse and reflects how energy is deposited by ions as described by the Bragg curve. It is likely to change along penetration depth and with track structure. Hence, ion beams of different Z but similar LET may differ radiobiologically. Construction of “biological” Bragg curves may improve modeling of ion action. There are also uncertainties on non-cancer effects of relevance in hadrontherapy. In fact, most experimental data are almost exclusively on tumour lethality and the Spread-Out Bragg Peak (SOBP), overlooking sub-lethal damage on normal cells at various positions along the Bragg curve. Further, little is known on non-targeted effects (NTE) by ion-irradiated normal cells expressing long-term sub-lethal damage. We studied Stress-Induced Premature Senescence (SIPS) by -galactosidase assay and chromosome aberrations (CA) by WCP-FISH and mFISH along the Bragg curve for several ion beams on 3 cell lines (AG01522 fibroblasts, MCF-10A breast epithelial cells, endothelial HUVEC cells). NTE occurrence was studied by medium-transfer from irradiated prematurely senescing cells at time points after irradiation on MCF10A and breast cancer epithelial MCF7 cells. To explore changing biological effectiveness along the Bragg curve we used up to 20 MeV 12C and 16O beams at a 3-MV Tandem accelerator (Department of Physics, Naples); and 60 MeV/u 16O and 20Ne beams at INFN-LNS cyclotron, Catania. Data show SIPS being effectively induced by ions, with a clear dependence on ion type and Bragg curve position, persisting for 2 months post exposure. CA data indicate a similar dependence, and the elevated frequency of complex-type CA agrees with these aberrations being a cytogenetic signature of high-LET ions. However, incidence of CA and SIPS point to a significantly greater efficiency of ion beams compared to x-rays even at very high LETs, contrary to the notion of a close-to-unity RBE above 200 keV/m. Onset of SIPS at ion beam entrance may have important implications for hadrontherapy patients. We also observed a significant bystander effect by senescing cells manifesting itself with an increase in tumour cell proliferation, in accord with reports of a Senescence-Associated Secretory Phenotype. Geant4 Monte-Carlo modeling is under way to correlate ion-track structure with such results

Medical research and multidisciplinary applications with laser-accelerated beams: the ELIMED netwotk at ELI-Beamlines

Laser accelerated proton beams represent nowadays an attractive alternative to the conventional ones and they have been proposed in different research fields. In particular, the interest has been focused in the possibility of replacing conventional accelerating machines with laser-based accelerators in order to develop a new concept of hadrontherapy facilities, which could result more compact and less expensive. With this background the ELIMED (ELIMED: ELI-Beamlines MEDical applications) research project has been launched by LNS-INFN researchers (Laboratori Nazionali del Sud-Istituto Nazionale di Fisica Nucleare, Catania, IT) and ASCR-FZU researchers (Academy of Sciences of the Czech Republic-Fyzikální ústar, Prague, Cz), within the pan-European ELI-Beamlines facility framework. Its main purposes are the demonstration of future applications in hadrontherapy of optically accelerated protons and the realization of a laser-accelerated ion transport beamline for multidisciplinary applications. Several challenges, starting from laser-target interaction and beam transport development, up to dosimetric and radiobiological issues, need to be overcome in order to reach the final goals. The design and the realization of a preliminary beam handling and dosimetric system and of an advanced spectrometer for high energy (multi-MeV) laser-accelerated ion beams will be shortly presented in this work

ELIMED, MEDical and multidisciplinary applications at ELI-Beamlines

ELI-Beamlines is one of the pillars of the pan-European project ELI (Extreme Light Infrastructure). It will be an ultra high-intensity, high repetition-rate, femtosecond laser facility whose main goal is generation and applications of high-brightness X-ray sources and accelerated charged particles in different fields. Particular care will be devoted to the potential applicability of laser-driven ion beams for medical treatments of tumors. Indeed, such kind of beams show very interesting peculiarities and, moreover, laser-driven based accelerators can really represent a competitive alternative to conventional machines since they are expected to be more compact in size and less expensive. The ELIMED project was launched thanks to a collaboration established between FZU-ASCR (ELI-Beamlines) and INFN-LNS researchers. Several European institutes have already shown a great interest in the project aiming to explore the possibility to use laser-driven ion (mostly proton) beams for several applications with a particular regard for medical ones. To reach the project goal several tasks need to be fulfilled, starting from the optimization of laser-target interaction to dosimetric studies at the irradiation point at the end of a proper designed transport beam-line. Researchers from LNS have already developed and successfully tested a high-dispersive power Thomson Parabola Spectrometer, which is the first prototype of a more performing device to be used within the ELIMED project. Also a Magnetic Selection System able to produce a small pencil beam out of a wide energy distribution of ions produced in laser-target interaction has been realized and some preliminary work for its testing and characterization is in progress. In this contribution the status of the project will be reported together with a short description of the of the features of device recently developed