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Purpose: To present the first direct experimental in vitro comparison of the biological effectiveness of rangeequivalent protons and carbon ion beams for Chinese hamsterovary cells exposed in a three-dimensional phantom using a pencil beam scanning technique and to compare the experimental data with a novel biophysical model. Methodsand Materials:Cell survivalwasmeasuredinthe phantomafter irradiation withtwo opposingfields,thus mimicking the typical patient treatment scenario. The novel biophysical model represents a substantial extension of the local effect model, previously used for treatment planning in carbon ion therapy for more than 400 patients, and potentially can be used to predict effectiveness of all ion species relevant for radiotherapy. A key feature of the new approach is the more sophisticated consideration of spatially correlated damage induced by ion irradiation. Results: The experimental data obtained for Chinese hamster ovary cells clearly demonstrate that higher cell killing is achieved in the target region with carbon ions as compared with protons when the effects in the entrance channel are comparable. The model predictions demonstrate agreement with these experimental data and with data obtained with helium ions under similar conditions. Good agreement is also achieved with relative biological effectiveness values reported in the literature for other cell lines for monoenergetic proton, helium, and carbon ions. Conclusion: Both the experimental data and the new modeling approach are supportive of the advantages of carbon ions as compared with protons for treatment-like field configurations. Because the model predicts the effectiveness for several ion species with similar accuracy, it represents a powerful tool for further optimization and utilization of the potential of ion beams in tumor therapy. 2010 Elsevier Inc. Ion beam therapy, Relative biological effectiveness (RBE), Biophysical model, Treatment planning.

The concept of the relative biological effectiveness (RBE) is essential for treatment planning in carbon ion therapy and for understanding the biological effects of high-LET radiation. As this quantity depends on many factors, both its experimental determination and the assessment of its uncertainty are not trivial. For the limiting case of zero dose, where the RBE takes its maximum value RBE(alpha), we present in this article a simple empirical-based approach to estimate its uncertainty. A Gaussian error calculus is applied to equally take into account both uncertainties from experiments with high- and low-LET radiation. From a theoretical point of view, we then infer, using a simple Monte Carlo model, the distribution of RBE(alpha) values. This illustrates why the conventional error propagation approach is inappropriate in some cases. In these cases, likewise also the error estimates have to be obtained with a more sophisticated approach. Uncertainties of RBE, visualized by error bars, are of importance for treatment planning and also for setting up a precision goal for predicting biophysical models such as the local effect model.

Purpose The objective of this experiment was to compare the oncogenic potential of carbon ion beams and conventional photon beams for use in radiotherapy. Methods and Materials The HeLa X human skin fibroblast cell line CGL1 was irradiated with carbon ions of three different energies (270, 100, and 11.4 MeV/u). Inactivation and transformation data were compared with those for 15 MeV photons. Results Inactivation and transformation frequencies for the 270 MeV/u carbon ions were similar to those for 15-MeV photons. The maximal relative biologic effectiveness (RBE α ) values for 100MeV/u and 11.4 MeV/u carbon ions, respectively, were as follows: inactivation, 1.6 ± 0.2 and 6.7 ± 0.7; and transformation per surviving cell, 2.5 ± 0.6 and 12 ± 3. The curve for dose-transformation per cell at risk exhibited a maximum that was shifted toward lower doses at lower energies. Conclusions Transformation induction per cell at risk for carbon ions in the entrance channel was comparable to that for photons, whereas for the lower energies, 100 MeV/u and 11 MeV/u, which are representative of the energies delivered to the tumor margins and volume, respectively, the probability of transformation in a single cell was greater than it was for photons. In addition, at isoeffective doses with respect to cell killing, the 11.4-MeV/u beam was more oncogenic than were photons.

To investigate the cytotoxic effect of high linear-energy transfer (LET) carbon irradiation on glioblastoma cells lines in combination with temozolomide (TMZ).The cell lines U87-MG expressing wild-type p53 and LN229 expressing both mutant and wild-type p53 were irradiated with monoenergetic carbon ion beams (LET 172 keV/microm) or an extended Bragg peak (LET 103 keV/microm) after treatment with 10 microM or 20 microM TMZ. Cytotoxicity was measured by a clonogenic survival assay, and cell growth as well as cell cycle progression, were examined.The p53 mutant was more sensitive to X-ray irradiation than the p53 wild type cell line, which was also expressed in a shorter G2 block. High LET carbon ions show an increased biological effectiveness in both cell lines, which is consistent with the predictive calculations by the Local Effect Model (LEM) introduced by Scholz et al. The cell line LN229 was more sensitive to TMZ treatment than the U87MG cell line expressing wild-type p53 only. The combination of TMZ and irradiation showed an additive effect in both cell lines.High LET carbon ion irradiation is significantly more effective for glioblastoma cell lines compared to photon irradiation. An additional treatment with TMZ may offer a great chance especially for several tumor types.

To investigate the influence of fractionation on cell survival and radiation induced premature differentiation as markers for early and late effects after X-rays and carbon irradiation. Normal human fibroblasts NHDF, AG1522B and WI-38 were irradiated with 250 kV X-rays, or 266 MeV/u, 195 MeV/u and 11 MeV/u carbon ions. Cytotoxicity was measured by a clonogenic survival assay or by determination of the differentiation pattern. Experiments with high-energy carbon ions show that fractionation induced repair effects are similar to photon irradiation. The RBE(10) values for clonogenic survival are 1.3 and 1.6 for irradiation in one or two fractions for NHDF cells and around 1.2 for AG1522B cells regardless of the fractionation scheme. The RBE for a doubling of post mitotic fibroblasts (PMF) in the population is 1 for both single and two fractionated irradiation of NHDF cells. Using 11 MeV/u carbon ions, no repair effect can be seen in WI-38 cells. The RBE(10) for clonogenic survival is 3.2 for single irradiation and 4.9 for two fractionated irradiations. The RBE for a doubling of PMF is 3.1 and 5.0 for single and two fractionated irradiations, respectively. For both cell lines the effects of high-energy carbon ions representing the irradiation of the skin and the normal tissue in the entrance channel are similar to the effects of X-rays. The fractionation effects are maintained. For the lower energy, which is representative for the irradiation of the tumor region, RBE is enhanced for clonogenic survival as well as for premature terminal differentiation. Fractionation effects are not detectable. Consequently, the therapeutic ratio is significantly enhanced by fractionated irradiation with carbon ions.

Accelerated ions have significant advantages for radiotherapy. From the physical side these are the inverse depth dose profile (the increase of the dose with penetration depth) and the finite range defined by the energy. Both factors, together with a small lateral scattering, provide an optimal dose distribution that makes ions an ideal tool for the treatment of deep-seated tumors close to radiosensitive organs. For carbon ions the positive physical dose distribution is potentiated by the increased relative biological effectiveness (RBE) towards the end of the particle range, which offers an additional advantage for slow growing radioresistent tumors. To exploit the high RBE to a maximum, a strict tumor conform dose application is necessary. Therefore, an active beam delivery system with an intensity-controlled rasterscan as well as a biologically optimized treatment planning based on the local effect model (LEM) have been developed at GSI. Positron emitters like 10 C, 11 C and 15 O that are produced by the primary beam can be used to monitor the stopping point of the primary beam inside the patient using Positron Emitting Tomograpy (PET) techniques. This lecture reviews the physical and biological basis of the therapy with accelerated ions and introduces the technical and mathematical tools necessary for the realisation. Positive early medical results will encourage the realisation of other planned centres.