Modern Physics Letters A

Hadrontherapy is today an established modality in cancer radiation therapy. Based on the superior ballistic and radiobiological properties of accelerated ions, this discipline experienced a remarkable growth in the last 20 years. This paper reviews the history of hadrontherapy, from the early days to the most recent developments. In particular, the evolution of proton and carbon ion therapy is presented together with a glance at future solutions such as single-room facilities.

Charged particle applications for radiotherapy are motivated by their specific advantages in terms of dose delivery and biological effect. These advantages have to a large extent originated from the peculiarities of ion beam energy deposition patterns in the medium on a microscopic, down to a nanoscopic scale. A large amount of research was conducted in this direction, especially in the last two decades, profiting also from the parallel investigations going on in radiation protection for space exploration.

The main biophysical aspects of charged particles, which are relevant to hadrontherapy are shortly reviewed in the present contribution, namely focusing on relative biological effectiveness (RBE), oxygen enhancement ratio (OER) and combination with radiosensitizers. A summary of present major research direction on both microscopic and macroscopic assessment of the specific mechanism of radiation damage will be given, as well as several open challenges for a better understanding of the whole process, which still limit the full exploitation of ion beams for radiotherapy.

History has shown that energetic particles can be useful for medical applications. From the time, in 1895 when Roentgen discovered X-rays, and in 1913 when Coolidge developed the vacuum X-ray tube, energetic particles have been an important tool for medicine. Development of the appropriate tool for effective and safe radiotherapy requires an in-depth understanding of the application and constraints. Various solutions are possible and choices must be analyzed on the basis of the suitability for meeting the requirements. Some of the requirements of charged particle therapy are summarized and various accelerator options are described and discussed.

Particle therapy is a field in remarkable development, with the goal of increasing the number of indications which could benefit from such treatments and the access to the therapy. The therapeutic usage of a particle beam defines the technical requirements of all the elements of the therapy chain: we summarize the main characteristics of accelerators, the beam line, the treatment room, the integrated therapy and imaging systems used in particle therapy. Aiming at a higher flexibility in the choice of treatments, an increasing number of centers around the world have chosen to equip their treatment rooms with gantries, rotating beam line structures that allow a complete flexibility in the choice of the treatment angle. We review the current designs. A particle therapy gantry though is a quite expensive structure, and future development will increasingly consider reducing the cost and the footprint.

Increasing the number of indications also means development in the delivery techniques and solving some of the issues which traditionally affected particle therapy, for example the precision of the delivery in presence of motion and the large penumbras for low depths. We show the current strategies in these fields, focusing on pencil beam scanning (PBS), and give some hints about future developments.

Over the last years, the interest in proton radiotherapy is rapidly increasing. Protons provide superior physical properties compared with conventional radiotherapy using photons. These properties result in depth dose curves with a large dose peak at the end of the proton track and the finite proton range allows sparing the distally located healthy tissue. These properties offer an increased flexibility in proton radiotherapy, but also increase the demand in accurate dose estimations. To carry out accurate dose calculations, first an accurate and detailed characterization of the physical proton beam exiting the treatment head is necessary for both currently available delivery techniques: scattered and scanned proton beams. Since Monte Carlo (MC) methods follow the particle track simulating the interactions from first principles, this technique is perfectly suited to accurately model the treatment head. Nevertheless, careful validation of these MC models is necessary. While for the dose estimation pencil beam algorithms provide the advantage of fast computations, they are limited in accuracy. In contrast, MC dose calculation algorithms overcome these limitations and due to recent improvements in efficiency, these algorithms are expected to improve the accuracy of the calculated dose distributions and to be introduced in clinical routine in the near future.

Ion therapy is an emerging technique used for the treatment of solid cancers. The monitoring of the dose delivered during such treatments and the on-line knowledge of the Bragg Peak (BP) position is still a matter of research. This paper reviews the current understanding of which radiation is produced during the interaction of the beam with the patient, the corresponding techniques developed to detect it and the level of understanding of the conversion between the emission spectra and the dose profile. It also performs a comparison between the different approaches.

Proton computed tomography (pCT) is a diagnostic method capable of in situ imaging the three-dimensional density distribution in a patient before irradiation with charged particle beams. Proposed long time ago, this technology has been developed by several groups, and may become an essential tool for advanced quality assessment in hadrontherapy. We describe the basic principles of the method, its performance and limitations as well as provide a summary of experimental systems and of results achieved.

The superior ballistic properties of ion beams may offer improved tumor-dose conformality and unprecedented sparing of organs at risk in comparison to other radiation modalities in external radiotherapy. However, these advantages come at the expense of increased sensitivity to uncertainties in the actual treatment delivery, resulting from inaccuracies of patient positioning, physiological motion and uncertainties in the knowledge of the ion range in living tissue. In particular, the dosimetric selectivity of ion beams depends on the longitudinal location of the Bragg peak, making in vivo knowledge of the actual beam range the greatest challenge to full clinical exploitation of ion therapy.

Nowadays, in vivo range verification techniques, which are already, or close to, being investigated in the clinical practice, rely on the detection of the secondary annihilation photons or prompt gammas, resulting from nuclear interaction of the primary ion beam with the irradiated tissue. Despite the initial promising results, these methods utilize a not straightforward correlation between nuclear and electromagnetic processes, and typically require massive and costly instrumentation. On the contrary, the long-term known, yet only recently revisited process of "ionoacoustics", which is generated by local tissue heating especially at the Bragg peak, may offer a more direct approach to in vivo range verification, as reviewed here.

Segmented ionization chambers represent a good solution to monitor the position, the intensity and the shape of ion beams in hadrontherapy. Pixel and strip chambers have been developed for both passive scattering and active scanning dose delivery systems. In particular, strip chambers are optimal for pencil beam scanning, allowing for spatial and time resolutions below 0.1 mm and 1 ms, respectively. The MATRIX pixel and the Strip Accurate Monitor for Beam Applications (SAMBA) detectors are described in this paper together with the results of several beam tests and industrial developments based on these prototypes.

The information of the dose is not sufficiently describing the biological effects of ions on tissue since it does not express the radiation quality, i.e. the heterogeneity of the processes due to the slowing-down and the fragmentation of the particles when crossing a target. Depending on different circumstances, the radiation quality can be determined using measurements, calculations, or simulations. Microdosimeters are the primary tools used to provide the experimental information of the radiation quality and their role is becoming crucial for the recent clinical developments in particular with carbon ion therapy. Microdosimetry is strongly linked to the biological effectiveness of the radiation since it provides the physical parameters which explicitly distinguish the radiation for its capability of damaging cells. In the framework of ion-beam therapy microdosimetry can be used in the preparation of the treatment to complement radiobiological experiments and to analyze the modification of the radiation quality in phantoms. A more ambitious goal is to perform the measurements during the irradiation procedure to determine the non-targeted radiation and, more importantly, to monitor the modification of the radiation quality inside the patient. These procedures provide the feedback of the treatment directly beneficial for the single patient but also for the characterization of the biological effectiveness in general with advantages for all future treatment. Traditional and innovative tools are currently under study and an outlook of present experience and future development is presented here.