International Journal of Radiation Oncology*Biology*Physics
Physics ContributionInterleaved Carbon Minibeams: An Experimental Radiosurgery Method With Clinical Potential
Introduction
Despite recent advancements in radiation therapy and radiosurgery, significant limitations remain. Although carbon therapy, being in clinical use in Japan 1, 2 and Germany (3) for more than 15 years, has shown remarkable effectiveness, particularly in treating radioresistant tumors, it still could benefit from a lower impact on nontargeted tissues to allow its administration at higher doses 2, 4. Interleaved carbon minibeams use arrays of parallel, thin planes (∼300 μm incident beam) (Fig. 1a, b) to produce a solid radiation field at the target. The present studies were carried out at the National Aeronautics and Space Agency Space Radiation Laboratory (NSRL), Brookhaven National Laboratory (BNL).
The technique is based on the well established tissue-sparing effect of arrays of parallel, thin or small beams. This effect was first detected in the 1950s by Zeman and Curtis at BNL using 25 MeV deuteron pencil beams of 25–1,000-μm diameter to expose the mouse cerebellum (5). Later it was verified with arrays of 25–37 μm planes of synchrotron X-rays (microbeams) at the National Synchrotron Light Source (NSLS), BNL (6) (“microbeam” refers here to <200 μm and minibeams to 200–700 μm beams). Soon afterward, the effect was explored in several other central nervous system (CNS) models at the NSLS 7, 8, 9 and European Synchrotron Radiation Facility in Grenoble, France 10, 11 including the brains of rats 6, 7, 9, mice (10), duck embryos (8), and suckling rats and piglets (11). Additional NSLS studies showed that X-ray minibeams as thick as 0.68 mm retain much of their tissue-sparing effect in the rat spinal cord and brain (12), and that two arrays of X-ray minibeams can be interleaved (interlaced) (Fig. 1c) to ablate a small target in the rat brain without significantly damaging the surrounding tissue 12, 13. All of these studies have been of single-dose fraction.
The mechanisms underlying microbeams’ and minibeams’ tissue sparing are the “dose–volume effect” (14), and the “microscopic, prompt tissue-repair effect” occurring only with submillimeter beams. The latter, studied with synchrotron X-ray microbeams of 25 μm and very high doses, has shown evidence for microvasculature repair starting within hours after the exposure (10). Microbeams’ overall tissue-sparing effect comes also from the dose–volume effect because only a fraction of the tissue’s volume is exposed to direct beams.
The first advantage of carbon beams over X-ray and gamma-rays for radiotherapy is their Bragg peak, largely concentrating the dose at the end of the beam’s trajectory (Fig. 2a). A uniform dose is produced at the target by modulating the beam’s energy (Fig. 2b). Carbon’s lack of exit dose allows implementation of the present method from four directions, thus reducing by twofold the entrance dose (Fig. 1b). Another carbon advantage is its high relative biological effectiveness (RBE) culminating at the Bragg peak 1, 2, 3, 4, which is particularly effective at producing double-strand breaks in DNA, thereby enhancing tumor cell killing. The cellular and molecular basis for carbon beams’ effect on high grade glioma cells is an active field of research (15). Also, carbon therapy produces a very sharp dose falloff of 80% to 20% at 1 mm or smaller, compared with up to 3–5 mm with X-rays and protons. Carbon minibeams gradually broaden as they pass through matter, an effect called multiple scattering or “angular straggling” (16). The effect, demonstrated in Fig. 2c by using a Bang-Gel phantom (17), excludes protons as potential minibeams because of their excessive broadening.
Section snippets
Irradiation of the rabbit brain with interleaved carbon minibeams: Basic features
All the studies were approved by the BNL’s Institutional Animal Care and Use committee. A male White New Zealand rabbit was used. The anesthetized animal was positioned upright (Fig. 3a) on the horizontal platform of a motorized rotating stage (Fig. 3b). The motorized stage was leveled and its rotation axis was aligned in the beam using a reference laser. To use a single range of beam energies for all four directions, the depth of the proximal side of the target from all directions was set
Producing the minibeam arrays
Carbon minibeams, 0.3 mm thick, spaced 1.05 mm on-center, were produced by positioning a tungsten “multislit collimator” in the path of a broad, uniform beam (Fig. 3c). Figure 3d shows the array’s pattern captured on a chromographic film positioned 10 cm from the collimator. The beam width, when scaled to the beam-spacing, is precisely 0.3 mm (i.e., the beam was perfectly parallel).
Monte Carlo simulations and the choice of minibeam spacing
We assessed the dose distribution of the carbon minibeams in the rabbit brain using the recently upgraded MCNPX
Discussion
Our studies suggest that segmented, thin carbon beams can be used to reduce the impact on the nontargeted tissues in carbon therapy. However, evaluation of the method’s potential in tumor therapy would require comparative studies with carbon broad beams using animal brain tumor models, which we plan to carry out.
The method’s advantages over radiosurgery with X-rays and gamma rays would include the advantages of carbon therapy, together with lower impact on the nontargeted tissues. The latter
Acknowledgments
The authors thank Saffa Ahmad, Kerry Bonti, Tiffany Bowman, Shravan Cheruku, I Hung Chiang, James Ciancarelli, Joseph Gatz III, Ioana Gearba, Benjamin Greenberg, Derek Lowenstein, Peggy L. Micca, Al Musella, Lynda Nwabuobi, Charles Pearson, MaryAnn Petry, Steve Rasmussen, Michael Sivertz, Wojtek Sobotka, Paul Wilson, Avril Woodhead, and Tom Zimmerman. NSRL is operated by National Aeronautics and Space Agency under a contract with Brookhaven National Laboratory and the US Department of Energy.
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Research was supported by grants from the Musella Brain Tumor Foundation, Brain Tumor Foundations of “Lauren’s First and Goal” and “Have a Chance”, Voices against Brain Cancer, Stony Brook Foundation (Allen G. Meek MD, PI), Stony Brook’s School of Medicine and the Office of Vice President for Research, Stony Brook’s Targeted Research Opportunities program, and Concerned Women of the Grove.
Conflicts of interest: Dilmanian and Meek have a pending patent application on the technology presented here.