Microbeam Radiotherapy (MRT)
Microbeam radiation therapy (MRT), a novel form of spatially fractionated radiotherapy (RT), uses arrays of synchrotron-generated X-ray microbeams (MB). MRT has been identified as a promising treatment concept that might be applied to patients with malignant central nervous system (CNS) tumours for whom, at the current stage of development, no satisfactory therapy is available yet. Preclinical experimental studies have shown that the CNS of healthy rodents and piglets can tolerate much higher radiation doses delivered by spatially separated MBs than those delivered by a single, uninterrupted, macroscopically wide beam. High-dose, high-precision radiotherapies such as MRT with reduced probabilities of normal tissue complications offer prospects of improved therapeutic ratios, as extensively demonstrated by results of experiments published by many international groups in the last two decades. The significance of developing MRT as a new RT approach cannot be understated. Up to 50% of cancer patients receive conventional RT, and any new treatment that provides better tumour control whilst preserving healthy tissue is likely to significantly improve patient outcomes.
Despite the technical and scientific advances of radiotherapy (RT) over the past decades, only palliative therapy is available for children and adults with a number of high-grade tumours. This often only extends the survival of individual patients by a few months. As an example, diffuse intrinsic pontine gliomas, which constitute 15% of all childhood brain tumours (600 new cases/year in Europe), are inoperable. Their response to radiation and chemotherapy is only transient, with patients having a median overall survival of 10 months.
Microbeam radiation therapy (MRT), a novel radiotherapy method invented by Slatkin and coworkers in 1992, is based on a spatial fractionation of synchrotron-generated X-ray beams. Spatial fractionation and the underlying laws of radiation physics were discovered by Alban Koehler at the beginning of the 20th century. It was used to reduce the extent of skin damage, a frequently occurring adverse effect of early radiotherapy. MRT was developed in a preclinical environment as a collaborative project involving physicists, engineers, biomedical scientists, and physicians, initially at the National Synchrotron Light Source at Brookhaven National Laboratory, Upton (USA), and later at the European Synchrotron Radiation Facility (ESRF), Grenoble (France).
MRT, based on the spatial fractionation of kilovoltage-energy X-ray beams, uses arrays of SRgenerated, collimated, planar, quasi-parallel microbeams (MBs; size, approximately 25–50 μm, spaced at 200–400 μm on centre). The synchrotron X-ray beam is segmented into a lattice of narrow, quasi-parallel, microplanar beams, typically 25- to 50-μm wide, separated by centre-to-centre distances (c-t-c) of 200–400 μm and delivered in a single treatment session, in a scanning mode. The very high in-beam MB ‘peak’ dose zones, in excess of 100 Gy, are separated by very low-dose ‘valley’ regions. These in-beam doses are orders of magnitude greater than those normally delivered in conventional RT. At a critical collimated beam width and separation in the order of tens and hundreds of microns, respectively, normal tissue can recover from hectogray exposure levels, which were previously considered to be lethal, whilst cancerous cells within the tumour are destroyed. Extremely high X-ray doses must be delivered at very high dose rates, within a very narrow time window, to prevent blurring of the MB tracks due to organ motion, so that the irradiation of an entire organ can be performed in a fraction of a second. The 6-GeV synchrotron ring at the ESRF is currently the only source of synchrotron radiation in Europe that is capable of generating intense X-ray microbeams, having a broad photon energy spectrum and fluence rates (i.e. X-ray beam intensities) high enough to deliver high absorbed physical radiation doses to deep targets in a scanning mode where a dedicated biomedical facility is available. Together with the adequate energy spectrum, the very low divergence of such X-ray beams is also conditional for preservation of the plane parallel beams and a sharp penumbra throughout the target, which is currently only feasible at such high energy synchrotron wiggler sources.
A Swiss-based research group for MRT has been intimately associated with the inventors of MRT for its development and validation over 20 years. The extensively equipped biomedical facility (ID17) at the ESRF, which is financed by 20 countries, acts as a central synchrotron RT research facility that plays a leading role in Europe and worldwide.
MRT for human patients
MRT for human patients requires a careful, multi-disciplinary evaluation of epidemiological, medical, logistical, and ethical considerations, including quality of life in comparison to life span, and endpoint definitions. Candidate populations could be adult patients with glioblastoma multiforme (approximately 20,000 new cases/year in Europe). Current standard treatment consists of surgery followed by chemoradiation and adjuvant temozolomide, but no standard of care exists for patients with recurrent tumours.
Paediatric patients with diffuse intrinsic pontine glioma (DIPG; approximately 600 new cases/year in Europe) would be an excellent candidate population. DIPG remains a most frustrating tumour in paediatric oncology. Because of the location of tumours and the difficulty in distinguishing tumour tissue from normal structures, surgical debulking is restricted by the substantial risk of morbidity and mortality. The mainstay of therapy for intrinsic pontine glioma has been RT. While there is evidence that conventional RT provides short-term benefits (i.e. a temporary improvement in neurological function and thus an increase in the quality of life), long-term results have been dismal and the overall survival time has not changed.
To safely conduct human clinical trials with MRT, new hardware and software need to be developed and tested. A patient-positioning system for MRT is currently available for small animals and larger animals such as pigs, dogs, and cats, up to a weight of 40 kg. Designing and building a patient-positioning system that will move a heavier human patient with the required exactness/spatial precision are therefore necessary. The therapy accuracy system used in the large animal trials was based on computed tomographic images. For clinical trials in humans, therapy planning which incorporates magnetic resonance imaging findings is desirable, as it provides higher spatial resolution. A marker system for reliable repositioning between image acquisitions and positioning for treatment could be either of the fiducial type or ensured by a stereotactic frame system. The preclinical veterinary trial in larger animals will improve understanding of the dosimetry, therapy planning, and therapeutic results for larger, deep-seated, spontaneous tumours.
The significance of developing MRT as a new RT approach cannot be understated. Up to 50% of cancer patients receive conventional RT. Especially for patients with highly malignant brain tumours, however, the improvement in quality of life and survival time with the currently available treatment schedules is unsatisfactory; any new treatment that provides better tumour control whilst preserving healthy tissue is likely to significantly improve patient outcomes. MRT has been identified as a most promising treatment concept for patients with malignant CNS tumours for whom, at the current stage of development, no satisfactory therapy is available yet.
MRT research is currently only possible at few centres in the world, with mainly the Australian Synchrotron in Melbourne and the ESRF in France having active programs for developing clinical applications. The availability of world-class facilities and the associated expertise of the investigators enable studies that have the potential to substantially improve RT for cancer and advance our understanding of fundamental tumour biology. ESRF is a most adequate source when moving to human trials, as the current dose rate assures no blurring of microbeams even within a slightly moving target such as the human brain.
Once we have demonstrated both the technical feasibility of using MRT in human patients and its therapeutic efficacy, results may have a major impact on the development of MB trials by using other available sources such as proton therapy, which could equally benefit from the tissue-sparing effects of beam microfractionation. The combination of MRT with drugs and/or other substances that enhance radiation effects, at optimised and tuneable X-ray energies, as well as its combination with gene-mediated therapies must be tested in order to establish whether these lead to considerable improvements compared to conventional RT alone.
The development of compact X-ray sources (presently under development in Europe by the France-based ThomX project), through which MRT may possibly be implemented, could make this promising technique available to a wider medical community.
Here are the most used equipment: