Introduction

 

Microbeam Radiation Therapy (MRT) uses highly collimated, quasi-parallel arrays of X-ray microbeams of 50-600 keV, produced by 3rd generation synchrotron sources. The main features of highly brilliant Synchrotron sources are an extremely high dose rate and very small beam divergence. High dose rates are necessary to deliver therapeutic doses in microscopic volumes, to avoid spreading of the microbeams by cardiosynchronous movement of the tissues.   The minimal beam divergence results in the obvious advantage of steeper dose gradients delivered to a tumor target, thus achieving a higher dose deposition in the target volume in fractions of seconds, with a sharper penumbra than that produced in conventional radiotherapy.

MRT research over the past 20 years has yielded many results from preclinical trials based on different animal models, including mice, rats, piglets and rabbits. Typically, MRT uses arrays of narrow (~25-75 micron-wide) microplanar beams separated by wider (100-400 microns centre to centre) microplanar spaces. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues and at the same time show a preferential damage of malignant tumor tissues.

Comparisons between broad beam irradiations and MRT indicate a higher therapeutic index in the latter. The hypothesis of a selective radiovulnerability by of the tumor vasculature versus normal blood vessels by MRT, and of the involved cellular and molecular mechanisms remains under investigation.

 

 

Materials and Methods

 

The production of such highly collimated, quasi-parallel arrays of X-ray microbeams ranging in energy from 50-600 keV is only feasible at a 3rd generation synchrotron source. The ESRF is currently among the most adequate sources for future clinical trials where the spreading of the microbeams due to cardiosynchronous movement of the tissues must be avoided by extremely rapid dose delivery. Because of the small beam divergence and the adequate photon spectrum (keV), a Multi Slit Collimator (MSC), inserted into the beam, produces and preserves steep dose gradients delivered to a tumor target within a fraction of seconds. The sharp dose gradients between peaks and valleys are preserved even after 15 cm of penetration of the microbeams in the depth of the tissue [1]. A 3D dose profile in a mouse head is presented in figure 1.

mrt_1.jpg

 

 

 

Figure 1: Monte Carlo simulated 3D dose profile of 9 parallel microbeams within a mouse head. The peaks at the entrance and at the exit show the increase in dose due to the presence of bone.

 

The wiggler source provides,  at a distance of 40 m from the storage ring, a beam of about 40 mm in width and 1 mm in height.   Thus,  to irradiate a  tumor volume of approximately 3 cm diameter, the target  must be swept vertically through the beam  in combination with a very fast shutter system [2] that defines  exactly the upper and lower limit of the irradiated target zone.

The production of very regular microbeams is a crucial aspect for MRT.  The development in instrumentation included  the very first variable MSC (Archer collimator [3]), then  the Tecomet MSC [4], and  recently  the advanced ESRF MSC (EMSC) produced from a solid tungsten carbide piece using new wire cutting techniques [5].

 

Hisorical overview in MRT and Summery of most important results

 

Spatial fractionation of ionizing radiation in the microscopic range was first reported in the sixties. A 25 µm-wide 22 MeV deuteron microbeam, used to simulate the effects of cosmic radiation (Curtis 1967)[6,7], failed to elicit cerebral in mice damage unless absorbed doses were over ~3000 Gy (Curtis 1963)[7,8]; the deuterons, however, reached only ~1.5 mm tissue depth.

    Later, it appeared that "microbeam radiation therapy" (MRT), using arrays of microplanar, synchrotron-generated X-ray beams, safely delivered radiation doses to contiguous normal animal brain that were much higher than maximum doses tolerated by the same normal tissues of animals or patients from any standard millimeters-wide radiosurgical beam (Laissue et al, 1998[9]). Preclinical experiments begun in 1995 at the ESRF and have been persued until today: Schweizer et al. 2000 [10]; Laissue et al, 1999, 2001 [11,12]; Blattmann et al, 2002 [13]; Bräuer-Krisch et al, 2005 [14], P. Regnard et al, 2008[15,16], and by R. Serduc 2008,2009 [17-19].

    MRT  delivers peak radiation doses up to fifty times higher than do other radiosurgeries and spares fast-growing, immature tissues such as the duck brain in ovo (Dilmanian et al, 2001[20]) and the chick chorio-allantoic membrane in vitro (Blattmann et al, 2005[13,21]). In vivo, the cerebella of normal suckling Sprague-Dawley rat pups and of normal weanling piglets were irradiated by arrays of parallel, synchrotron-wiggler-generated X-ray microbeams in doses covering the MRT-relevant range (˜50-600 Gy). Most animals developed normally over at least one year after irradiation (Laissue et al, 1999 [11,12],  An example of a histological section of the hindbrain of the weaned piglets is shown in figure 2.

 mrt_2.jpg

 

Figure 2: Microbeam irradiated normal CNS of weaned piglets (1.5cm x 1.5cm   ~28 mm-wide beams ~210 mm on center, 625 Gy). The histological sections look normal, except for "stripes" due to the dropout of neuronal/astroglial nuclei. This sharp spatial fractionation is preserved throughout the cerebellum. No tissue necrosis, hemorrhage or demyelination was observed.

 

In preclinical trials, intracranial rat  9LGS  and mouse EMT-6 carcinomas have been treated by variants of MRT; the growth of nearly every tumour was suppressed, at least temporarily, and many tumours were ablated (Laissue et al, 1998[9]; Dilmanian et al, 2002, 2003[22,23]; Smilowitz et al, 2006[24]). Even the extraordinarily radiation-resistant and fast-growing murine squamous cell carcinoma VII has been palliated by MRT (Miura et al, 2006[25]). For the intracerebral 9LGS, estimates of the therapeutic index of MRT versus broad-beam treatment indicate a ˜5-fold advantage, with a normal tissue tolerance = 10-fold higher for peak microplanar versus seamless doses of radiation (Dilmanian et al, 2002[22]). In conventional radiotherapy, the effect of changing an irradiation parameter, e.g., the dose fractionation schedule, is predictable. Conversely, methods to predict the effect of varying MRT parameters such as array width and height, slit width, center-to-center spacing, number of ports, energy spectrum, dose microdistribution and schedules for temporal fractionation (Serduc et al, 2009[18]) or geometric adjustments (Bräuer-Krisch et al, 2005[14,26]) of multidirectional MRT are only beginning to be developed.

     

References:

 

 

[1]    E. Siegbahn, E. Brauer-Krisch, J. Stepanek, H. Blattmann, J. Laissue and A. Bravin Dosimetric studies of microbeam radiation therapy (MRT) with Monte Carlo simulations, Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 548 (2005) 54-58.

[2]    M. Renier, T. Brochard, C. Nemoz and W. Thomlinson A White-beam Fast-Shutter for Microbeam Radiation Therapy at the ESRF, Nucl. Instrum. Methods A 479 (2002) 656-660

[3]    D. Archer Collimator for producing an array of microbeams, United States Patent, 1998.

[4]    E. Bräuer-Krisch, A. Bravin, E. Siegbahn, A., L. Zhang, J. Stepanek, H. Blattmann, D.N. Slatkin, J.O. Gebbers, M. Jasmin and J. Laissue Characterization of a tungsten/gas multislit collimator for microbeam radiation therapy at the European Synchrotron Radiation Facility., Review of scientific instruments 76 (2005) 1-7.

[5]    E. Bräuer-Krisch, H. Requardt, T. Brochard, G. Berruyer, M. Renier, J. Laissue and A. Bravin New technology enables precision multi slits collimators for MRT (Microbeam Radiation Therapy), Accepetd Review of Scientific Instruments (2009).

[6]    H. Curtis The use of deuteron microbeam for simulating the biological effect of heavy cosmic-ray particles, Radiat Res supplement 7 (1967) 250-257.

[7]    H. Curtis The microbeam as a tool in radiobiology, Adv Biol Med Phys 175 (1963) 207-224.

[8]    H.J. Curtis The interpretation of microbeam experiments for manned space flight, Radiat Res Suppl 7 (1967) 258-264.

[9]    J.A. Laissue, G. Geiser, P.O. Spanne, F.A. Dilmanian, J.O. Gebbers, M. Geiser, X.Y. Wu, M.S. Makar, P.L. Micca, M.M. Nawrocky, D.D. Joel and D.N. Slatkin Neuropathology of ablation of rat gliosarcomas and contiguous brain tissues using a microplanar beam of synchrotron-wiggler-generated X rays, Int J Cancer 78 (1998) 654-660.

[10]    P.M. Schweizer, P. Spanne, M. Di Michiel, U. Jauch, H. Blattmann and J.A. Laissue Tissue lesions caused by microplanar beams of synchrotron-generated X-rays in Drosophila melanogaster, Int J Radiat Biol 76 (2000) 567-574.

[11]    J.A. Laissue, N. Lyubimova, H.P. Wagner, D.W. Archer, D.N. Slatkin, M. Di Michiel, C. Nemoz, M. Renier, E. Bräuer-Krisch, P.O. Spanne, J.-O. Gebbers, K. Dixon and H. Blattmann Microbeam radiation therapy, Proc. Of SPIE, Denver, USA, 1999, pp. 38-45.

[12]    J.A. Laissue, H. Blattmann, D. Michiel, D.N. Slatkin, N. Lyubimova, R. Guzman, A. Zimmermann, S. Birrer, T. Bey, P. Kircher, R. Stettler, R. Fatzer, A. Jaggy, H.M. Smilowitz, E. Bräuer-Krisch, A. Bravin, G. Le Duc, C. Nemoz, M. Renier, W. Thomlinson, J. Stepanek and H.P. Wagner The weanling piglet cerebellum: a surrogate for tolerance to MRT (microbeam radiation therapy) in pediatric neuro-oncology, Proc. of SPIE, Washington, 2001, pp. 65-73.

[13]    H. Blattmann, W. Burkard, V. Djonov, M. DiMichiel, E. Brauer, J. Stepanek, A. Bravin, J.-O. Gebbers and J. Laissue Microbeam irradiation in the chorio-allantoic membrane (CAM) of chicken embryo, Strahlenther. Onkol 178 (2002) 118.

[14]    E. Bräuer-Krisch, H. Requardt, P. Regnard, S. Corde, E. Siegbahn, G. Leduc, T. Brochard, H. Blattmann, J. Laissue and A. Bravin New irradiation geometry for microbeam radiation therapy, Phys Med Biol 50 (2005) 3103-3111.

[15]    P. Regnard, E. Bräuer-Krisch, I. Tropes, J. Keyrilainen, A. Bravin and G. Le Duc Enhancement of survival of 9L gliosarcoma bearing rats following intrcerbral delivery of drugs in combination with microbeam radiation therapy, Europ J Radiol 68 (2008) S 151-155.

[16]    P. Regnard, G.L. Duc, E. Bräuer-Krisch, I. Tropres, E.A. Siegbahn, A. Kusak, C. Clair, H. Bernard, D. Dallery, J.A. Laissue and A. Bravin Irradiation of intracerebral 9L gliosarcoma by a single array of microplanar x-ray beams from a synchrotron: balance between curing and sparing, Phys Med Biol 53 (2008) 861-878.

[17]    R. Serduc, A. Bouchet, E. Bräuer-Krisch and G. Le Duc Microbeam radiation therapy parameters optimization for rat brain tumors palliation. Influence of the microbeam width at constant valley dose, Submited Phys Med Biol (2009).

[18]    R. Serduc, E. Brauer-Krisch, A. Bouchet, L. Renaud, T. Brochard, A. Bravin, J.A. Laissue and G. Le Duc First trial of spatial and temporal fractionations of the delivered dose using synchrotron microbeam radiation therapy, J Synchrotron Radiat 16 (2009) 587-590.

[19]    R. Serduc, B. Lemasson and A. Bouchet Rat brain tumor pallation by microbeam radiation therapy, the vascular component., Under preparation (2009).

[20]    F.A. Dilmanian, G.M. Morris, G. Le Duc, X. Huang, B. Ren, T. Bacarian, J.C. Allen, J. Kalef-Ezra, I. Orion, E.M. Rosen, T. Sandhu, P. Sathe, X.Y. Wu, Z. Zhong and H.L. Shivaprasad Response of avian embryonic brain to spatially segmented x-ray microbeams, Cell Mol Biol 47 (2001) 485-493.

[21]    H. Blattmann, J.-O. Gebbers, E. Brauer-Krisch, A. Bravin, G. Le Duc, W. Burkard, D. Michiel, V. Djonov, D.N. Slatkin, J. Stepanek and J. Laissue Applications of synchrotron X-rays to radiotherapy, Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 548 (2005) 17-22.

[22]    F.A. Dilmanian, T.M. Button, G. Le Duc, N. Zhong, L.A. Pena, J.A. Smith, S.R. Martinez, T. Bacarian, J. Tammam, B. Ren, P.M. Farmer, J. Kalef-Ezra, P.L. Micca, M.M. Nawrocky, J.A. Niederer, F.P. Recksiek, A. Fuchs and E.M. Rosen Response of rat intracranial 9L gliosarcoma to microbeam radiation therapy, Neuro-oncol 4 (2002) 26-38.

[23]    F.A. Dilmanian, G.M. Morris, N. Zhong, T. Bacarian, J.F. Hainfeld, J. Kalef-Ezra, L.J. Brewington, J. Tammam and E.M. Rosen Murine EMT-6 carcinoma: high therapeutic efficacy of microbeam radiation therapy, Radiat Res 159 (2003) 632-641.

[24]    H.M. Smilowitz, H. Blattmann, E. Bräuer-Krisch, A. Bravin, M.D. Michiel, J.O. Gebbers, A.L. Hanson, N. Lyubimova, D.N. Slatkin, J. Stepanek and J.A. Laissue Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy for advanced intracerebral rat 9L gliosarcomas, J Neurooncol 78 (2006) 135-143.

[25]    M. Miura, H. Blattmann, E. Bräuer-Krisch, A. Bravin, A.L. Hanson, M.M. Nawrocky, P.L. Micca, D.N. Slatkin and J.A. Laissue Radiosurgical palliation of aggressive murine SCCVII squamous cell carcinomas using synchrotron-generated X-ray microbeams, Br J Radiol 79 (2006) 71-75.

[26]    E. Bräuer-Krisch, H. Requardt, P. Regnard, S. Corde, E. Siegbahn, A., G. Leduc, H. Blattmann, J. Laissue and A. Bravin Exploiting geometrical irradiation possibilities in MRT application, Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 548 (2005) 69-71.

 

 

Further References in MRT:

 

 

    A. Koehler Zur Roentgentiefentherapie mit Massendose, Muenchner Medizinische Wochenzeitschrift 56 (1909) 2314-2316.


    J. Penagaricano, R. Griffin, P. Corry, E. Moros, Y. Yan and V. Ratanatharathorn Spatially fractionated (GRID) therapy for large and bulky tumors, Journal of Ark Med Soc 105 (2009) 263-265.


    D.N. Slatkin, P. Spanne, F.A. Dilmanian and M. Sandborg Microbeam radiation therapy, Med Phys 19 (1992) 1395-1400.


    J. Laissue, P. Spanne, F.A. Dilmanian, J.O. Gebbers and D.N. Slatkin Zell- und Gewebeläsionen nach räumlich fraktionierter Mikro-Bestrahlung des ZNS mit Synchrotron Photonen., Schweiz. Med. Wochenschr. 122 (1992) 16-27.


    D.N. Slatkin, P. Spanne, F.A. Dilmanian, J.O. Gebbers and J.A. Laissue Subacute neuropathological effects of microplanar beams of x-rays from a synchrotron wiggler, Proc Natl Acad Sci U S A 92 (1995) 8783-8787.


    D.D. Joel, R.G. Fairchild, J.A. Laissue, S.K. Saraf, J.A. Kalef-Ezra and D.N. Slatkin Boron neutron capture therapy of intracerebral rat gliosarcomas, Proc Natl Acad Sci U S A 87 (1990) 9808-9812.


    H. Wagner Cancer in childhood and suppotive care, Support care cancer 7 (1999) 293-294.

    R.K. Mulhern, T.E. Merchant, A. Gajjar, W.E. Reddick and L.E. Kun Late neurocognitive sequelae in survivors of brain tumours in childhood, Lancet Oncol 5 (2004) 399-408.


    K. Ribi, C. Relly, M.A. Landolt, F.D. Alber, E. Boltshauser and M.A. Grotzer Outcome of medulloblastoma in children: long-term complications and quality of life, Neuropediatrics 36 (2005) 357-365.


     J.C. Crosbie, I. Svalbe, S.M. Midgley, N. Yagi, P.A. Rogers and R.A. Lewis A method of dosimetry for synchrotron microbeam radiation therapy using radiochromic films of different sensitivity, Phys Med Biol 53 (2008) 6861-6877.


    F.Z. Company and B.J. Allen Calculation of microplanar beam dose profiles in a tissue/ lung/tissue phantom, Phys Med Biol 43 (1998) 2491-2501.


    J. Stepanek, H. Blattmann, J.A. Laissue, N. Lyubimova, M. Di Michiel and D.N. Slatkin Physics study of microbeam radiation therapy with PSI-version of Monte Carlo code GEANT as a new computational tool, Med Phys 27 (2000) 1664-1675.


    M. De Felici, R. Felici, M. Sanchez del Rio, C. Ferrero, T. Bacarian and F.A. Dilmanian Dose distribution from x-ray microbeam arrays applied to radiation therapy: An EGS Monte Carlo study, Med Phys 32 (2005) 2455-2463.


    J. Spiga, E.A. Siegbahn, E. Bräuer-Krisch, P. Randaccio and A. Bravin The GEANT4 toolkit for microdosimetry calculations: application to microbeam radiation therapy (MRT), Med Phys 34 (2007) 4322-4330.


    I. Orion, A.B. Rosenfeld, F.A. Dilmanian, F. Telang, B. Ren and Y. Namito Monte Carlo simulation of dose distributions from a synchrotron-produced microplanar beam array using the EGS4 code system, Phys Med Biol 45 (2000) 2497-2508.


    E.A. Siegbahn, E. Brauer-Krisch, A. Bravin, H. Nettelbeck, M.L. Lerch and A.B. Rosenfeld MOSFET dosimetry with high spatial resolution in intense synchrotron-generated x-ray microbeams, Med Phys 36 (2009) 1128-1137.


    H. Nettelbeck, G.J. Takacs, M.L. Lerch and A.B. Rosenfeld Microbeam radiation therapy: a Monte Carlo study of the influence of the source, multislit collimator, and beam divergence on microbeams, Med Phys 36 (2009) 447-456.


    E. Schültke, B.H. Juurlink, K. Ataelmannan, J. Laissue, H. Blattmann, E. Brauer-Krisch, A. Bravin, J. Minczewska, J. Crosbie, H. Taherian, E. Frangou, T. Wysokinsky, L.D. Chapman, R. Griebel and D. Fourney Memory and survival after microbeam radiation therapy, Eur J Radiol 68 (2008) S142-146.


     Y. Prezado, G. Fois, G. Le Duc and A. Bravin Gadolinium dose enhancement studies in microbeam radiation therapy, Med Phys 36 (2008) 3568-3574.


    C. Alric, R. Serduc, C. Mandon, J. Taleb, G. Le Duc, A. Le Meur-Herland, C. Billotey, P. Perriat, S. Roux and O. Tillement Gold nanoparticles designed for combining dual modality imaging and radiotherapy, Gold Bulletin 41 (2008) 90-97.


     N. Zhong, G.M. Morris, T. Bacarian, E.M. Rosen and F.A. Dilmanian Response of rat skin to high-dose unidirectional x-ray microbeams: a histological study, Radiat Res 160 (2003) 133-142.

     R. Serduc, B. Lemasson and A. Bouchet Rat brain tumor pallation by microbeam radiation therapy, the vascular component., Under preparation (2009).


     P. Romanelli and D.J. Anschel Radiosurgery for epilepsy, Lancet Neurol 5 (2006) 613-620.


    F.A. Dilmanian, Z. Zhong, T. Bacarian, H. Benveniste, P. Romanelli, R. Wang, J. Welwart, T. Yuasa, E.M. Rosen and D.J. Anschel Interlaced x-ray microplanar beams: a radiosurgery approach with clinical potential, Proc Natl Acad Sci U S A 103 (2006) 9709-9714.


    R. Serduc, N. Pannetier, A. Bouchet, T. Brochard, T. Christen, G. Berruyer, J. Laissue, F. Esteve, C. Remy, E. Barbier, A. Bravin, G. Le Duc and E. Bräuer-Krisch High flux low energy photons challenge conventional high energy radiation therapy for CNS lesions. Focused high dose delivery is achievable with synchrotron generated x-rays., submitted for publication (2009).


    M. Ptaszkiewicza, E. Bräuer-Krisch, M. Klosowski, L. Czopyk and P. Olko TLD dosimetry for microbeam radiation therapy at the ESRF, Radiation Measurements 43 (2008) 990-993.


    E. Bräuer-Krisch, A. Bravin, M. Lerch, A. Rosenfeld, J. Stepanek, M. Di Michiel and J.A. Laissue MOSFET dosimetry for microbeam radiation therapy at the European Synchrotron Radiation Facility, Med Phys 30 (2003) 583-589.


    E.C. Mackonis, N. Suchowerska, M. Zhang, M. Ebert, D.R. McKenzie and M. Jackson Cellular response to modulated radiation fields, Phys Med Biol 52 (2007) 5469-5482.