Particle therapy in the future of precision therapy.

The first hospital-based treatment facilities for particle therapy started operation about thirty years ago. Since then, the clinical experience with protons and carbon ions has grown continuously and more than 200,000 patients have been treated to date. The promising clinical results led to a rapidly increasing number of treatment facilities and many new facilities are planned or under construction all over the world. An inverted depth-dose profile combined with potential radiobiological advantages make charged particles a precious tool for the treatment of tumours that are particularly radioresistant or located nearby sensitive structures. A rising number of trials have already confirmed the benefits of particle therapy in selected clinical situations and further improvements in beam delivery, image guidance and treatment planning are expected. This review summarises some physical and biological characteristics of accelerated charged particles and gives some examples of their clinical application. Furthermore, challenges and future perspectives of particle therapy will be discussed.

ÖGRO survey on radiotherapy capacity in Austria : Status quo and estimation of future demands.

BACKGROUND: A comprehensive evaluation of the current national and regional radiotherapy capacity in Austria with an estimation of demands for 2020 and 2030 was performed by the Austrian Society for Radiation Oncology, Radiobiology and Medical Radiophysics (ÖGRO). MATERIALS AND METHODS: All Austrian centers provided data on the number of megavoltage (MV) units, treatment series, fractions, percentage of retreatments and complex treatment techniques as well as the daily operating hours for the year 2014. In addition, waiting times until the beginning of radiotherapy were prospectively recorded over the first quarter of 2015. National and international epidemiological prediction data were used to estimate future demands. RESULTS: For a population of 8.51 million, 43 MV units were at disposal. In 14 radiooncological centers, a total of 19,940 series with a mean number of 464 patients per MV unit/year and a mean fraction number of 20 (range 16-24) per case were recorded. The average re-irradiation ratio was 14%. The survey on waiting times until start of treatment showed provision shortages in 40% of centers with a mean waiting time of 13.6 days (range 0.5-29.3 days) and a mean maximum waiting time of 98.2 days. Of all centers, 21% had no or only a limited ability to deliver complex treatment techniques. Predictions for 2020 and 2030 indicate an increased need in the overall number of MV units to a total of 63 and 71, respectively. CONCLUSION: This ÖGRO survey revealed major regional differences in radiooncological capacity. Considering epidemiological developments, an aggravation of the situation can be expected shortly. This analysis serves as a basis for improved public regional health care planning.

SYRA3 COST Action--Microbeam radiation therapy: Roots and prospects.

Microbeam radiation therapy (MRT) is an irradiation modality for therapeutic purposes which uses arrays of collimated quasi parallel microbeams, each up to 100 µm wide, to deliver high radiation doses. Several studies have reported the extraordinary tolerance of normal tissues to MRT irradiation; conversely, MRT has been shown to be highly efficient on tumor growth control. The original and most widely developed application of MRT, yet in the preclinical phase, consists in using spatially fractionated X-ray beams issued from a synchrotron radiation source in the treatment of brain tumors. More recently, MRT has been tested in successful pioneering assays to reduce or interrupt seizures in preclinical models of epilepsy. The MRT concept has also been extended to proton therapy. The development of MRT towards its clinical implementation is presently driven by an EU-supported consortium of laboratories from 16 countries within the COST Action TD1205 (SYRA3). The results of the first SYRA3 workshop on "Radiation Therapy with Synchrotron Radiation: Achievements and Challenges" held in Krakow (Poland) during March 25-26 2014 are summarized in this issue with an overview presented in this paper. The papers reflect the multidisciplinary international activities of SYRA3. The topics covered in this focus issue include medical physics aspects, pre-clinical studies, clinical applications, and an industrial perspective; finally an outlook towards future prospects of compact sources and proton microbeams.

Particle therapy for noncancer diseases.

Radiation therapy using high-energy charged particles is generally acknowledged as a powerful new technique in cancer treatment. However, particle therapy in oncology is still controversial, specifically because it is unclear whether the putative clinical advantages justify the high additional costs. However, particle therapy can find important applications in the management of noncancer diseases, especially in radiosurgery. Extension to other diseases and targets (both cranial and extracranial) may widen the applications of the technique and decrease the cost/benefit ratio of the accelerator facilities. Future challenges in this field include the use of different particles and energies, motion management in particle body radiotherapy and extension to new targets currently treated by catheter ablation (atrial fibrillation and renal denervation) or stereotactic radiation therapy (trigeminal neuralgia, epilepsy, and macular degeneration). Particle body radiosurgery could be a future key application of accelerator-based particle therapy facilities in 10 years from today.

International Conference on Advances in Radiation Oncology (ICARO): outcomes of an IAEA meeting.

The IAEA held the International Conference on Advances in Radiation Oncology (ICARO) in Vienna on 27-29 April 2009. The Conference dealt with the issues and requirements posed by the transition from conventional radiotherapy to advanced modern technologies, including staffing, training, treatment planning and delivery, quality assurance (QA) and the optimal use of available resources. The current role of advanced technologies (defined as 3-dimensional and/or image guided treatment with photons or particles) in current clinical practice and future scenarios were discussed.ICARO was organized by the IAEA at the request of the Member States and co-sponsored and supported by other international organizations to assess advances in technologies in radiation oncology in the face of economic challenges that most countries confront. Participants submitted research contributions, which were reviewed by a scientific committee and presented via 46 lectures and 103 posters. There were 327 participants from 70 Member States as well as participants from industry and government. The ICARO meeting provided an independent forum for the interaction of participants from developed and developing countries on current and developing issues related to radiation oncology.

[Is proton beam therapy the future of radiotherapy? Part I: clinical aspects]. / La protonthérapie: avenir de la radiothérapie? Première partie: aspects cliniques.

Proton beam therapy uses positively charged particles, protons, whose physical properties improve dose-distribution (Bragg peak characterized by a sharp distal and lateral penumbra) compared with conventional photon-based radiation therapy (X-ray). These ballistic advantages apply to the treatment of deep-sited tumours located close to critical structures and requiring high-dose levels. [60-250 MeV] proton-beam therapy is now widely accepted as the "gold standard" in specific indications in adults--ocular melanoma, chordoma and chondrosarcoma of the base of skull --and is regarded as a highly promising treatment modality in the treatment of paediatric malignancies (brain tumours, sarcomas…). This includes the relative sparing of surrounding normal organs from low and mid-doses that can cause deleterious side-effects such as radiation-induced secondary malignancies. Other clinical studies are currently testing proton beam in dose-escalation evaluations, in prostate, lung, hepatocellular cancers, etc. Clinical validation of these new indications appears necessary. To date, over 60,000 patients worldwide have received part or all of their radiation therapy program by proton beams, in approximately 30 treatment facilities.

Respiratory motion management in particle therapy.

Clinical outcomes of charged particle therapy are very promising. Currently, several dedicated centers that use scanning beam technology are either close to clinical use or under construction. Since scanned beam treatments of targets that move with respiration most likely result in marked local over- and underdosage due to interplay of target motion and dynamic beam application, dedicated motion mitigation techniques have to be employed. To date, the motion mitigation techniques, rescanning, beam gating, and beam tracking, have been proposed and tested in experimental studies. Rescanning relies on repeated irradiations of the target with the number of particles reduced accordingly per scan to statistically average local misdosage. Specific developments to prohibit temporal correlation between beam scanning and target motion will be required to guarantee adequate averaging. For beam gating, residual target motion within gating windows has to be mitigated in order to avoid local misdosage. Possibly the most promising strategy is to increase the overlap of adjacent particle pencil beams laterally as well as longitudinally to effectively reduce the sensitivity against small residual target motion. The most conformal and potentially most precise motion mitigation technique is beam tracking. Individual particle pencil beams have to be adapted laterally as well as longitudinally according to the target motion. Within the next several years, it can be anticipated that rescanning as well as beam gating will be ready for clinical use. For rescanning, treatment planning margins that incorporate the full extent of target motion as well as motion induced density variations in the beam paths will result in reduced target conformity of the applied dose distributions. Due to the limited precision of motion monitoring devices, it seems likely that beam gating will be used initially to mitigate interplay effects only but not to considerably decrease treatment planning margins. Then, in the next step, beam gating, based on more accurate motion monitoring systems, provides the possibility to restore target conformity as well as steep dose gradients due to reduced treatment planning margins. Accurate motion monitoring systems will be required for beam tracking. Even though beam tracking has already been successfully tested experimentally, full clinical implementation requires direct feedback of the actual target position in quasireal time to the treatment control system and can be anticipated to be several more years ahead.

The radiotherapy clinical trials projects at the ESRF: technical aspects.

The radiotherapy clinical trials projects, both aiming at treating aggressive brain tumors, require several major modifications and new constructions at the ESRF ID17 Biomedical beamline. The application of the Stereotactic Synchrotron Radiation Therapy (SSRT) technique mainly necessitates an upgrade of the existing patient positioning system, which was formerly used for the angiography program. It will allow for accurate positioning, translation and rotation of the patient during the treatment. For the Microbeam Radiation Therapy (MRT) clinical trials project, a new white beam hutch will be constructed to accommodate a dedicated patient positioning system. Consequently, the existing control hutches and the related installations will also be completely refurbished. Furthermore, the foreseen installation of a second X-ray source, which will allow doubling the currently available photon flux at high energies, requires a redesign of most optical components to handle the increased power and power densities. Starting from the current ID17 Biomedical beamline layout, the paper will present an update of the different modification/construction projects, including the general organization and planning.

Internal high linear energy transfer (LET) targeted radiotherapy for cancer.

High linear energy transfer (LET) radiation for internal targeted therapy has been a long time coming on to the medical therapy scene. While fundamental principles were established many decades ago, the clinical implementation has been slow. Localized neutron capture therapy, and more recently systemic targeted alpha therapy, are at the clinical trial stage. What are the attributes of these therapies that have led a band of scientists and clinicians to dedicate so much of their careers? High LET means high energy density, causing double strand breaks in DNA, and short-range radiation, sparing adjacent normal tissues. This targeted approach complements conventional radiotherapy and chemotherapy. Such therapies fail on several fronts. Foremost is the complete lack of progress for the control of primary GBM, the holy grail for cancer therapies. Next is the inability to regress metastatic cancer on a systemic basis. This has been the task of chemotherapy, but palliation is the major application. Finally, there is the inability to inhibit the development of lethal metastatic cancer after successful treatment of the primary cancer. This review charts, from an Australian perspective, the developing role of local and systemic high LET, internal radiation therapy.

Prostate brachytherapy: brief history and the evolution of the different techniques

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Using the frame averaging of aS500 EPID for IMRT verification.

In this study, we evaluated the use of aS500 EPID for the verification of IMRT beam delivery, using the synchronous, frame-averaging acquisition. In this approach, an EPID continuously integrates frames while irradiated by an IMRT field; the averaged image is then converted to a dose profile using a linear calibration curve, and is compared with the planned profiles using a linear-regression model, which returns an index sigma (root mean squared error) for the goodness of fit. We identified several potential errors in this acquisition mode: missing data between the start of irradiation and imaging, and from the last (incomplete) frame, which we proved are insignificant for IMRT fields; and EPID dead time during irradiation stemming from data transfer, which we successfully corrected for clinical MU (>100). We compared the measured relative profiles and central axis dose of 25 prostate fields with the planned ones. Applying our correction methods, very good agreement was obtained between the measured and planned profiles with a mean sigma of 1.9% and a standard deviation of 0.5%; for central-axis dose the agreement was better than 2.0%. We conclude that the aS500 is an effective tool for verification of IM beam delivery in the range of clinical MU (>100) settings. Although the vender is developing an upgrade to fix similar problems, our results demonstrate that the current configuration with simple correction schemes can achieve satisfactory results.

TG-51: experience from 150 institutions, common errors, and helpful hints.

The Radiological Physics Center (RPC) is a resource to the medical physics community for assistance regarding dosimetry procedures. Since the publication of the AAPM TG-51 calibration protocol, the RPC has responded to numerous phone calls raising questions and describing areas in the protocol where physicists have had problems. At the beginning of the year 2000, the RPC requested that institutions participating in national clinical trials provide the change in measured beam output resulting from the conversion from the TG-21 protocol to TG-51. So far, the RPC has received the requested data from approximately 150 of the approximately 1300 institutions in the RPC program. The RPC also undertook a comparison of TG-21 and TG-51 and determined the expected change in beam calibration for ion chambers in common use, and for the range of photon and electron beam energies used clinically. Analysis of these data revealed two significant outcomes: (i) a large number (approximately 1/2) of the reported calibration changes for photon and electron beams were outside the RPC's expected values, and (ii) the discrepancies in the reported versus the expected dose changes were as large as 8%. Numerous factors were determined to have contributed to these deviations. The most significant factors involved the use of plane-parallel chambers, the mixing of phantom materials and chambers between the two protocols, and the inconsistent use of depth-dose factors for transfer of dose from the measurement depth to the depth of dose maximum. In response to these observations, the RPC has identified a number of circumstances in which physicists might have difficulty with the protocol, including concerns related to electron calibration at low energies (R50<2 cm), and the use of a cylindrical chamber at 6 MeV electrons. In addition, helpful quantitative hints are presented, including the effect of the prescribed lead filter for photon energy measurements, the impact of shifting the chamber depth for photon depth-dose measurements, and the impact of updated stopping-power data used in TG-51 versus that used in TG-21, particularly for electron calibrations.

Biological factors influencing the RBE of neutrons: implications for their past, present and future use in radiotherapy.

The recent resurgence of interest in fast-neutron therapy, particularly for the treatment of prostate cancer, warrants a review of the original radiobiological basis for this modality and the evolution of these concepts that resulted from subsequent experimentation with the fast-neutron beams used for randomized clinical trials. It is clear from current radiobiological knowledge that some of the postulates that formed the mechanistic basis for past clinical trials were incorrect. Such discrepancies, along with the inherent physical disadvantages of neutron beams in terms of collimation and intensity modulation, may partially account for the lack of therapeutic benefit observed in many randomized clinical trials. Moreover, it is equally apparent that indiscriminate prescription of fast-neutron therapy is likely to lead to an adverse clinical outcome in a proportion of patients. Hence any renewed efforts to establish a niche for this modality in clinical radiation oncology will necessitate the development of a triage system that can discriminate those patients who might benefit from fast-neutron therapy from those who might be harmed by it. In the future, fast-neutron therapy might be prescribed based upon the relative status of appropriate molecular parameters that have a differential impact upon radiosensitivity to photons compared to fast neutrons.

A challenge for high-precision radiation therapy: the case for hadrons.

Developments in Hadron therapy, i.e., fast neutrons, protons, pions, heavy ions and boron neutron capture therapy are reviewed. For each type of particle, operational and closed facilities are listed as well as planned new facilities. Improvements in clinical results have always been linked to technological developments and better physical selectivity of the irradiation. Exploring the benefit of further improvement in dose localization expected from protons and conformal therapy is the challenge for the coming years. The radiobiological rationale for high-LET radiation in cancer treatment, proposed in the fifties, is still valid and has not been contradicted by recent radiobiological findings. This justifies the planning of a therapy facility where protons and heavy ions (carbon ions) could be applied, under optimal physical and technical conditions. Appropriate selection between low- and high-LET radiation for a particular tumor is indeed a radiobiological problem, independent of technical development.