High-energy beams of charged nuclear particles (protons and heavier ions) offer significant advantages for the treatment of deep-seated local tumors in comparison to conventional megavolt photon therapy. Their physical depth-dose distribution in tissue is characterized by a small entrance dose and a distinct maximum (Bragg peak) near the end of range with a sharp fall-off at the distal edge. Taking full advantage of the well-defined range and the small lateral beam spread, modern scanning beam systems allow delivery of the dose with millimeter precision. In addition, projectiles heavier than protons such as carbon ions exhibit an enhanced biological effectiveness in the Bragg peak region caused by the dense ionization of individual particle tracks resulting in reduced cellular repair. This makes them particularly attractive for the treatment of radio-resistant tumors localized near organs at risk. While tumor therapy with protons is a well-established treatment modality with more than 60 000 patients treated worldwide, the application of heavy ions is so far restricted to a few facilities only. Nevertheless, results of clinical phase I-II trials provide evidence that carbon-ion radiotherapy might be beneficial in several tumor entities. This article reviews the progress in heavy-ion therapy, including physical and technical developments, radiobiological studiesmore » and models, as well as radiooncological studies. As a result of the promising clinical results obtained with carbon-ion beams in the past ten years at the Heavy Ion Medical Accelerator facility (Japan) and in a pilot project at GSI Darmstadt (Germany), the plans for new clinical centers for heavy-ion or combined proton and heavy-ion therapy have recently received a substantial boost.« less

Heavy-ion tumor therapy: Physical and radiobiological benefits

The effect of ionising radiation is influenced by the dose, the dose rate, and the quality of the radiation. Before 1990, dose-equivalent quantities were defined in terms of a quality factor, Q(L), that was applied to the absorbed dose at a point in order to take into account the differences in the effects of different types of radiation. In its 1990 recommendations, the ICRP introduced a modified concept. For radiological protection purposes, the absorbed dose is averaged over an organ or tissue, T, and this absorbed dose average is weighted for the radiation quality in terms of the radiation weighting factor, wR, for the type and energy of radiation incident on the body. The resulting weighted dose is designated as the organ- or tissue-equivalent dose, HT. The sum of the organ-equivalent doses weighted by the ICRP organ-weighting factors, wT, is termed the effective dose, E. Measurements can be performed in terms of the operational quantities, ambient dose equivalent, and personal dose equivalent. These quantities continue to be defined in terms of the absorbed dose at the reference point weighted by Q(L). The values for wR and Q(L) in the 1990 recommendations were based on a review of the biological and other information available, but the underlying relative biological effectiveness (RBE) values and the choice of wR values were not elaborated in detail. Since 1990, there have been substantial developments in biological and dosimetric knowledge that justify a re-appraisal of wR values and how they may be derived. This re-appraisal is the principal objective of the present report. The report discusses in some detail the values of RBE with regard to stochastic effects, which are central to the selection of wR and Q(L). Those factors and the dose-equivalent quantities are restricted to the dose range of interest to radiation protection, i.e. to the general magnitude of the dose limits. In special circumstances where one deals with higher doses that can cause deterministic effects, the relevant RBE values are applied to obtain a weighted dose. The question of RBE values for deterministic effects and how they should be used is also treated in the report, but it is an issue that will demand further investigations. This report is one of a set of documents being developed by ICRP Committees in order to advise the ICRP on the formulation of its next Recommendations for Radiological Protection. Thus, while the report suggests some future modifications, the wR values given in the 1990 recommendations are still valid at this time. The report provides a scientific background and suggests how the ICRP might proceed with the derivation of wR values ahead of its forthcoming recommendations.

https://journals.sagepub.com/doi/pdf/10.1016/S0146-6453%2803%2900024-1

Relative biological effectiveness(RBE), quality factor(Q), and radiation weighting factor(WR)

We describe a novel approach to treatment planning for heavy-ion radiotherapy based on the local effect model (LEM) which allows us to calculate the biologically effective dose not only for the target region but also for the entire irradiation volume. LEM is ideally suited for use as an integral part of treatment planning code systems for active dose shaping devices like the GSI raster scan system. Thus it has been incorporated into our standard treatment planning system for ion therapy (TRiP). Single intensity modulated fields can be optimized with respect to a homogeneous biologically effective dose. The relative biological effectiveness (RBE) is calculated separately for each voxel of the patient CT. Our radiobiologically oriented code system has been used since 1995 for the planning of irradiation experiments with cell cultures and animals such as rats and minipigs. It has been in regular and successful use for patient treatment planning since 1997.

https://iopscience.iop.org/article/10.1088/0031-9155/45/11/314/pdf

Treatment planning for heavy-ion radiotherapy: calculation and optimization of biologically effective dose.

Purpose: The LET position of the RBE maximum and its dependence on the cellular repair capacity was determined for carbon ions. Hamster celllines of differing repair capacity were irradiated with monoenergetic carbon ions. RBE values for cell inactivation at different survival levels were determined and the differences in the RBE-LET patterns were compared with the individual sensitivity to photon irradiation of the different cell lines. Material and methods: Three hamster cell lines, the wild-type cell lines V79 and CHO-K1 and the radiosensitive CHO mutant xrs5, were irradiated with carbon ions of different energies (2.4-266.4MeV/u) and LET values (13.7-482.7keV/mum) and inactivation data were measured in comparison to 250kV x-rays. Results: For the repair-proficient cell lines a RBE maximum was found at LET values between 150 and 200keV/mum. For the repair-deficient cell line the RBE failed to show a maximum and decreased continuously for LET values above 100keV/mum. Conclusions: The carbon RBE-LET rela...

RBE for carbon track-segment irradiation in cell lines of differing repair capacity

advances made in the ® eld of molecular biology Purpose: A brief review is presented of the basic concepts in track when PCR (polymerase chain reaction), X- and structure and the relative merit of various theoretical approaches neutron spectroscopy techniques became available. adopted in Monte-Carlo track-structure codes are examined. In Within the space of two decades, many important the second part of the paper, a formal cluster analysis is techniques that were in the domain of very specialist introduced to calculate cluster-distance distributions. M ethod: Total experimental ionization cross-sections were least- research groups have become widely available, oa square ® tted and compared with the calculation by various the-shelf, to all researchers. In this context, `track theoretical methods. Monte-Carlo track-structure code Kurbuc structure’ is a new tool for the study of the mechanwas used to examine and compare the spectrum of the secondary isms of radiation ea ects. A question frequently asked electrons generated by using functions given by Born± Bethe, is, to what extent the use of track-structure calculaJain± Khare, Gryzinsky, Kim± Rudd, Mott and Vriens’ theories. The cluster analysis in track structure was carried out using the tions has facilitated and extended our understanding k-means method and Hartigan algorithm. of the mechanisms of radiation damage? Track strucR esults: Data are presented on experimental and calculated total ture is barely two decades old and is still at the ionization cross-sections: inverse mean free path (IMFP) as a developmental stage, but during this time it has made function of electron energy used in Monte-Carlo track-structure a considerable contribution not only to the undercodes; the spectrum of secondary electrons generated by dia erent functions for 500 eV primary electrons; cluster analysis for 4 MeV standing of the mechanisms of radiation ea ect in and 20 MeV a-particles in terms of the frequency of total cluster human cells but also in practical aspects of radiation energy to the root-mean-square (rms) radius of the cluster and therapy (Scholz et al. 1997), scanning electron microdia erential distance distributions for a pair of clusters; and ® nally scopy (Parikh 1979), Auger electron spectroscopy relative frequency distribution for energy deposited in DNA,

Track structure in radiation biology : theory and applications

A simplified method for the calculation of mammalian cell survival after charged particle irradiation is presented that is based on the track structure model of Scholz and Kraft [1, 2]. Utilizing a modified linear-quadratic relation for the x-ray survival curve, one finds that the model yields linear-quadratic relations also for heavy ion irradiation. If survival is calculated as a function of specific energy, z, in the cell nucleus--thus reducing the stochastic fluctuations of energy deposition--the increase in slope of the survival curve and therefore the coefficient beta z can be estimated with sufficient accuracy from the initial slope, alpha z. This permits the tabulation of the coefficients alpha z for the particle types and energies of interest, and subsequent fast calculations of survival levels at any point in a mixed particle beam. The complexity of the calculations can thereby be reduced in a wide range of applications, which permits the rapid calculations that are required for treatment planning in heavy ion therapy. The validity of the modified computations is assessed by the comparison with explicit calculations in terms of the original model and with experimental results for track-segment conditions. The model is then used to analyze the influence of beam fragmentation on the biological effect of charged particle beams penetrating to different depths in tissue. In addition, cell-survival rates after neuron irradiation are computed from the slowing-down spectra of secondary charged particles and are compared to experimental observations.

Computation of cell survival in heavy ion beams for therapy. The model and its approximation

Cell cycle delays in V79 Chinese hamster cells induced by heavy ion exposure have been investigated using flow cytometry. Synchronous cell populations in G1, S and late-S G2/M phase were used, which were prepared by centrifugal elutriation. Cells were irradiated with particles from Z = 10 (neon) up to 96 (uranium) in the energy range from 2·4 to 17·4 MeV/u and the LET range from 415 to 16225 keV/μm at the UNILAC at GSI, Darmstadt. For comparison, experiments with 250kV X-rays were performed. For light particles like neon, cell cycle perturbations comparable with those after X-ray irradiation were found, and with increasing LET an increasing delay per particle traversal was observed. For the highest LET values extended delavy in G1, S and G2/M phase were detected immediately after irradiation. A large fraction of the cells remained in S or G2/M phase up to 48 h or longer after irradiation: they probably died in interphase. The prolongation of delays with increasing LET is in contrast with inactivation cros...

Cell cycle delays induced by heavy ion irradiation of synchronous mammalian cells.

Induction of chromosome aberrations in mammalian cells after heavy ion exposure.

Cellular and subcellular effect of heavy ions: a comparison of the induction of strand breaks and chromosomal aberration with the incidence of inactivation and mutation.

The radiobiological effects of heavy charged particles are of fundamental interest for the understanding of radioprotection problems in manned space flights and for the increasing use of heavy ions in radiotherapy. Therefore, an increasing number of radiobiological experiments are performed at heavy-ion accelerators. In these experiments biological targets such as, for instance, cultures of living mammalian cells have to be irradiated under sterile conditions and atmospheric pressure. The experimental solution of these and other biology-specific problems is discussed and a general outline of the experiments is given.

W. Kraft-Weyrather

Papers

Computation of cell survival in heavy ion beams for therapy. The model and its approximation

Cell cycle delays induced by heavy ion irradiation of synchronous mammalian cells.

Induction of chromosome aberrations in mammalian cells after heavy ion exposure.

Cellular and subcellular effect of heavy ions: a comparison of the induction of strand breaks and chromosomal aberration with the incidence of inactivation and mutation.

The preparation of biological targets for heavy-ion experiments up to 20 MeV/u