Characteristics of Carbon Ion Beam- Physics in C-Ion RT at NIRS / HIMAC -Naruhiro MatsufujiNational Institute of Radiological Sciences, Research Center for Charged Particle Therapy\nAbstractPhysics is expected to play an important role in utilizing heavy ions for radiotherapy and further improvement or optimization. Technical improvements and accumulated knowledge in the behaviour of heavy ions promote the improvements in various aspects related to the physics in carbon ion radiotherapy (C-ion RT) at HIMAC such as beam or biological model. The production of secondary neutron is also of concern from the viewpoint of high QOL after the C-ion RT. Those recent status and updates related to the medical physics for ongoing C-ion RT at HIMAC are reported.\nIntroductionElevating energy loss toward range end associated with increasing biological effectiveness renders heavy ions such as carbon ions attractive for treating deep-seated tumors. The modality was first realized as a pioneering study at the Lawrence Berkeley Laboratory (LBL) in the United States. Next to LBL, National Institute of Radiological Sciences (NIRS) of Japan started the heavy ion radiotherapy at Heavy Ion Medical Accelerator in Chiba (HIMAC) since 1994 with carbon ions. The outcome in the past 16 years is proving the expectation toward heavy ion radiotherapy as true.The absorbed dose, quantity of energy given by radiation, is the most fundamental parameter to be controlled in radiotherapy. It is true even in the C-ion RT; however, different from conventional radiations, therapeutic beam contains various kind and energy of particles due to the nuclear reactions between incident carbon ions and target nuclei. It makes the spatial distribution of therapeutic beams and its biological effectiveness complex in comparison to conventional radiations. In order to make the best use of heavy ions for radiotherapy, it is indispensable to understand the behaviour of the therapeutic beam precisely.\nMaterials and MethodsBeam modelBiological effectiveness of the charged particles is, as the first approximation, considered proportional to LET (linear energy transfer), the amount of energy released in a unit length. However, even LET is identical, lateral distribution of energy deposition (track structure) is different between different particle species in microscopic viewpoint. This difference in the track structure causes a particle-species dependency in biological response when expressed as a function of LET, and makes it indispensable to understand the radiation quality, i.e., the fluence and LET on each particle species at any region of interest for a precise estimation of the biological effect of the therapeutic beam.In our current passive beam delivery, lateral distribution of the radiation quality is, as the first approximation, regarded as constant due to the sharp falloff of penumbra and the equilibrium between incoming and outgoing particles to and from the region of interest in the irradiation field. Fig. 1 and 2 show measured axial fluence and LET distribution of therapeutic carbon beam measured at HIMAC (1). Our current beam model for the passive beam delivery is based on this one-dimensional distribution of absorbed dose as well as radiation qualities.In order to estimate the distribution of radiation quality in the irradiation field in detail, or in order to form the irradiation field by a scanning with narrow pencil-like beams, it is strongly required to understand the spatial distribution of the radiation quality. The deflection of primary particles in a medium is well described by Molieres multiple scattering theory (2) while multiple scattering alone is not sufficient to account for the distribution of the fragment particles. We measured the angular distribution of the fragment particles from mono-energetic 290 MeV/n 12C beam through a nuclear reaction in a thick water target and revealed that the deflection of fragment particles in a substance is reproduced well when considering one additional term representing an extra lateral kick at the production point of the fragment to the Molieres multiple scattering formula (3). This additional term can be explained as a transfer of the intra-nucleus Fermi momentum of a projectile to the fragment, and its extent obeys the expectation derived from the Goldhaber model (4). Based on these studies, a semi-analytical beam transportation code was developed for energetic heavy-ion beams by which the three dimensional distribution of radiation quality can be calculated for each species of particles (5). In the code the production of secondary and tertiary fragments is considered and the effects of Fermi momentum transfer is taken into account at their production point. Despite its simplicity, the developed code can reproduce the experimental result well. We have installed the code to our new treatment planning system for the coming scanning irradiation. \n Fig. 1 Particle composition of therapeutic 290Fig. 2 Axial LET distribution of the therapeutic MeV/n of carbon beam (SOBP 60 mm) as a 290 MeV/n of carbon beam (SOBP 60 mm) in function of thickness in water.water.\nBiological response modelAmong various cell lines, HSG (human salivary gland) was chosen as our standard in our current model (6). The response of the HSG cell has a small shoulder in their survival curve, and belongs to the early-responding tissues. Then, spread-out Bragg peak (SOBP) was designed to achieve a flat cell survival probability (10%) for the HSG cells in the entire SOBP region. The LQ (linear-quadratic) model is used to reproduce the HSG response for therapeutic beam including high- and low-LET particles. The parameters  and  in the LQ model were obtained as dose-averaging coefficients  and  of monoenergetic beams over the spectrum of the SOBP beam. The response of the HSG cells for carbon SOBP beam is found to be equivalent at the point where the dose-averaged LET value is 80 keV/m to the NIRS neutron beam that was once used for radiotherapy. The relationship between absorbed dose distributions and biological response of the HSG cells is regarded relatively identical in the clinical situation, i.e., if we realize the flat biological response in the SOBP region for the HSG cells, clinical response should be also flat, though the RBE value can be different. As the clinical RBE of the fast neutron radiotherapy at NIRS was observed as 3.0, the clinical dose distribution of the therapeutic carbon beam is finally deduced by equally multiplying a fixed factor, the ratio between the clinical and biological RBE value at the point where the dose-averaged LET is 80 keV/m, to the entire biological SOBP. This scheme is summarized as fig. 3. Then ridge filters were manufactured to realize the various widths of SOBP for C-ion RT at HIMAC regardless of tumor type or fraction size in order to understand the clinical response of various tissues against carbon ions. The appropriateness of this SOBP design has been confirmed through an analysis of our clinical result in terms of tumor control probability (7). From fundamental viewpoint, biological effect caused by radiations is considered to be originated from lesions caused in DNA strands. The DNA has a diameter of about 2nm and enclosed in a cell nucleus that is about 10m in diameter. The energy deposition in such a minute region is strongly affected by statistic randomness. Here the LET, a macroscopic averaged value, is no longer appropriate to tell the life and death of a cell. Microdosimetric-kinetic model (MKM) (8) is one of the attempts to explain the biological effect of radiations based on the microdosimetric information. Damage to a cell is characterized with a specific energy or a lineal energy (corresponds to absorbed dose and LET in a macroscopic view, respectively) in domains assumed inside a cell nucleus. As the microdosimetric quantities are assessable by measurement, we can estimate the biological effectiveness of the therapeutic beam at any region of interest. The biological response of our standard HSG cell to various kinds and energy of ions is successfully reproduced by the MKM with measured specific energy for any particle species (9). Fig. 3 Current design of clinical SOBP at HIMAC\n-Production of secondary neutronsUnlike other charged fragment particles, secondary neutrons are largely scattered out in space. As a result, the secondary neutrons show wide spatial and energetic distributions. Absorbed dose delivered by the secondary neutrons is in average sparse; however, the neutron loses its energy in a matter by colliding with proton(s) and makes dense energy deposition in the vicinity of the collision point. The resultant local but high biological effectiveness is considered as one of the main causes of late effect after certain period of the C-ion RT. We have attempted to measure the dose delivered by neutrons to surrounding normal tissues in charged particle radiotherapy from the viewpoint of estimating the risk of their causing secondary cancer to the patient. A thick water phantom was irradiated with beams of 12C-290 MeV/n or 1H-160 MeV. Bonner sphere (6LiI(Eu) scintillator inserted) was placed around the phantom in order to measure the emitted neutrons. A commercial neutron rem counter was also used in the measurement for the sake of comparison. As an example, fig. 4 shows a comparison of ambient dose equivalent between the carbon and proton beam as an angle from beam axis by changing the aperture (MLC) size. The distribution of secondary neutrons is isotropic in the proton field while strong forward peak is observed in carbon field. The measurements suggest that the dose delivered by neutrons is less than 1 % of the total dose delivered by carbon ions. This dose level was found to be comparable to that obtained with protons (10).\nConclusion16 years have passed since the beginning of clinical trials for carbon therapy at HIMAC. Splendid clinical results derived for most cases would validate our first modeling of the therapeutic beam. To brush up the ongoing therapy modality and establish the optimal heavy-ion therapy in the next stage, both theoretical and experimental efforts must be paid further on the interactions of particles including neutrons with a matter and resultant biological effectiveness through the thorough understanding of the clinical outcomes.\n\nFig. 4 Ambient dose equivalent of secondary neutrons from carbon and proton beams.References Matsufuji N, Fukumura, A, Komori M et al. Influence of fragment reaction of relativistic heavy charged particles on heavy ion radiotherapy. Phys. Med. Biol. 2003: 48:1605-1623.Moliere G. Theorie der Streuung Schneller Geladener Teilchen. II. Mehrfach-und Vielfachstreuung Z. Naturforsch. 1948:3a:78–97.Matsufuji N, Komori M, Urakabe E et al. Spatial fragment distribution from a therapeutic pencil-like carbon beam in water. Phys. Med. Biol. 2005: 50: 3393-3403.Goldhaber A S. Statistical models of fragmentation processes. Phys. Lett. B: 1974: 53:306–308.Inaniwa T, Furukawa T, Matsufuji, N. et al. Clinical ion beams: semi-analytical calculation of their quality. Phys. Med. Biol. 2007: 52: 7261-7279.Kanai T, Endo M, Minohara S et al. Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy. Int. J. Radiat. Oncology Biol. Phys. 1999: 44: 201-210.Kanai T, Matsufuji N, Miyamoto T et al. Examination of GyE system for HIMAC carbon therapy. Int. J. Radiat. Oncology Biol. Phys. 2006: 64: 650-656.Hawkins R. B. A microdosimetric-kinetic model of cell death from exposure to ionizing radiation of any LET, with experimental and clinical applications. Int. J. Radiat. Biol. 1996: 69: 739-751.Kase Y, Kanai, T, Matsufuji, N et al. Biophysical calculation of cell survival probabilities using amorphous track structure models for heavy-ion irradiation. Phys. Med. Biol. 2008: 53: 37-59.Yonai S, Matsufuji N, Kanai T et al. Measurement of neutron ambient dose equivalent in passive carbon-ion and proton radiotherapies. Med. Phys. 2008: 35: 4782-4792.Joint Symposium: From Cancer Biology to Photon and Carbon Ion Radiation Therap
