Physics Contribution
Interleaved Carbon Minibeams: An Experimental Radiosurgery Method With Clinical Potential

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Purpose

To evaluate the efficacy of “interleaved carbon minibeams” for ablating a 6.5-mm target in a rabbit brain with little damage to the surrounding brain. The method is based on the well-established tissue-sparing effect of arrays of thin planes of radiation.

Methods and Materials

Broad carbon beams from the National Aeronautics and Space Agency Space Radiation Facility at Brookhaven National Laboratory were segmented into arrays of parallel, horizontal, 0.3-mm-thick planar beams (minibeams). The minibeams’ gradual broadening in tissues resulted in 0.525-mm beam thickness at the target’s proximal side in the spread-out Bragg peak. Interleaving was therefore implemented by choosing a 1.05 mm beam spacing on-center. The anesthetized rabbit, positioned vertically on a stage capable of rotating about a vertical axis, was exposed to arrays from four 90° angles, with the stage moving up by 0.525 mm in between. This produced a solid radiation field at the target while exposing the nontargeted tissues to single minibeam arrays. The target “physical” absorbed dose was 40.2 Gy.

Results

The rabbit behaved normally during the 6-month observation period. Contrast magnetic resonance imaging and hematoxylin and eosin histology at 6 months showed substantial focal target damage with little damage to the surrounding brain.

Conclusion

We plan to evaluate the method’s therapeutic efficacy by comparing it with broad-beam carbon therapy in animal models. The method’s merits would combine those of carbon therapy (i.e., tight target dose because of the carbon’s Bragg-peak, sharp dose falloff, and high relative biological effectiveness at the target), together with the method’s low impact on the nontargeted tissues. The method’s smaller impact on the nontargeted brain might allow carbon therapy at higher target doses and/or lower normal tissue impact, thus leading to a more effective treatment of radioresistant tumors. It should also make the method more amenable to administration in either a single dose fraction or in a small number of fractions.

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.

References (20)

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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.

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