Grade of eosinophilia versus symptoms in patients with dysphagia and esophageal eosinophilia.

The aim of this study was to assess whether the symptom severity and health-related quality of life (HRQL) of patients with dysphagia and esophageal eosinophilia correlate with disease activity as expressed by the number of eosinophils in the esophageal mucosa. This study included newly diagnosed (n = 58) or relapsed patients (n = 7), where 40% were diagnosed in connection with esophageal bolus impaction. The mean age was 45 years (19-88), and 74% were men. Symptoms and HRQL were recorded using the Watson Dysphagia Scale (WDS), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Oesophageal Module 18 and the Short Form-36 Questionnaire. Histological samples gathered from the proximal and distal esophageal mucosa were stained using both hematoxylin and eosin (HE) and an immunohistochemical (IHC) technique against 'Eosinophil Major Basic Protein,' and the peak number of eosinophils per high-power field was assessed. More eosinophils were detected after IHC staining than HE staining (P < 0.001). No correlation was found between symptoms or the HRQL and the number of eosinophils. However, higher numbers of eosinophils at the proximal esophagus were found in patients with concomitant bolus impaction (IHC P < 0.05 and HE P < 0.05) and could serve as a risk marker.

Bacterial flora of the human oral cavity, and the upper and lower esophagus.

This reference study aims to survey the bacterial flora of the healthy lower human esophagus and to compare it with that of the upper esophagus and oral mucosa. The use of biopsies, in addition to brush samples, allows inclusion of not only transient bacteria present on the surface but also bacteria residing in the epithelia, and the yield of the two methods can be compared. Forty patients scheduled for surgery for reasons with no known influence on esophageal flora and with no symptoms or endoscopic signs of esophageal disease were included. Samples were collected from the oral, upper esophageal, and lower esophageal mucosa using sealed brushes and biopsy forceps. Colonies cultivated on agar plates were classified and semiquantified. Twenty-three different bacterial species were identified, with similar strains present at the three sites. The most common group of bacteria was viridans streptococci, with an occurrence rate in brush samples and biopsies of 98% and 95%, respectively. The median number of species occurring in the oral cavity, upper esophagus, and lower esophagus was between 3 and 4 (range 0-7). The total number of species in the oral cavity was significantly higher when compared with either level in the esophagus, while the yields obtained by brush and biopsy sampling were highly correlated. Hence, the normal human esophagus is colonized with a resident bacterial flora of its own, which has similarities to that of the oral mucosa. There are diverse species that make up this flora, although in relatively low amounts. The most frequent inhabitants of the esophagus are streptococci, with an occurrence rate in brush samples and biopsies of 95-98%. Comparative studies of patients with eosinophilic esophagitis and gastroesophageal reflux disease are warranted.

The influence of RBE variations in a clinical proton treatment plan for a hypopharynx cancer.

Currently, most clinical range-modulated proton beams are assumed to have a fixed overall relative biological effectiveness (RBE) of 1.1. However, it is well known that the RBE increases with depth in the spread-out Bragg peak (SOBP) and becomes about 10% higher than mid-SOBP RBE at 2 mm from the distal edge (Paganetti 2003 Technol. Cancer Res. Treat. 2 413-26) and can reach values of 1.3-1.4 in vitro at the distal edge (Robertson et al 1975 Cancer 35 1664-77, Courdi et al 1994 Br. J. Radiol. 67 800-4). We present a fast method for applying a variable RBE correction with linear energy transfer (LET) dependent tissue-specific parameters based on the alpharef/betaref ratios suitable for implementation in a treatment planning system. The influence of applying this variable RBE correction on a clinical multiple beam proton dose plan is presented here. The treatment plan is evaluated by RBE weighted dose volume histograms (DVHs) and the calculation of tumour control probability (TCP) and normal tissue complication probability (NTCP) values. The variable RBE correction yields DVHs for the clinical target volumes (CTVs), a primary advanced hypopharynx cancer and subclinical disease in the lymph nodes, that are slightly higher than those achieved by multiplying the absorbed dose with RBE=1.1. Although, more importantly, the RBE weighted DVH for an organ at risk, the spinal cord is considerably increased for the variable RBE. As the spinal cord in this particular case is located 8 mm behind the planning target volume (PTV) and hence receives only low total doses, the NTCP values are zero in spite of the significant increase in the RBE weighted DVHs for the variable RBE. However, high NTCP values for the non-target normal tissue were obtained when applying the variable RBE correction. As RBE variations tend to be smaller for in vivo systems, this study-based on in vitro data since human tissue RBE values are scarce and have large uncertainties-can be interpreted as showing the upper limits of the possible effects of utilizing a variable RBE correction. In conclusion, the results obtained here still indicate a significant difference in introducing a variable RBE compared to applying a generic RBE of 1.1, suggesting it is worth considering such a correction in clinical proton therapy planning, especially when risk organs are located immediately behind the target volume.

Fractionated, stereotactic proton beam treatment of cerebral arteriovenous malformations.

OBJECTIVES: To evaluate the therapeutic efficiency and adverse effects of stereotactic proton beam treatment of cerebral arteriovenous malformations (AVM). MATERIAL AND METHODS: Twenty-six patients treated in Uppsala during 1991-97 were included (men = 14, women = 12; mean age = 39, range = 23-64). The nidus volumes ranged from 0.3 to 102 ml (mean = 24, median = 13). The follow-up included clinical evaluation, magnetic resonance imaging (and/or computed tomography) every 6-12 months for 3 years and final angiography. RESULTS: The volume changes at final follow-up in AVMs >25 ml were -89, -85, -44, -29, -7, 0, 0, +5 and +18 (%); in AVMs 11-24 ml, -100, -100, -97, -92 and 0 (%); and in AVMs <10 ml, -100, -100, -100, -100, -100, -99, -98, -50, -0 and +40 (%). Two patients were lost to follow-up due to cerebral haemorrhage and myocardial infarction. Radiology displayed significant perifocal oedema in one patient and slight oedema in four patients. Of nine patients with epilepsy, seven became seizure-free after therapy while two continued to suffer from seizures. CONCLUSION: Proton beam irradiation is successful in a relatively high proportion of intermediate and large-sized cerebral AVMs. The adverse effects are acceptable. The advantage of proton treatment compared with gamma knife and LINAC stereotactic irradiation is that protons can irradiate even large volumes with a very sharp dose profile against normal surroundings. Thus, proton beam irradiation is a valuable option in the treatment of AVMs larger than 10 ml.

Comparison of Monte Carlo calculated electron slowing-down spectra generated by 60Co gamma-rays, electrons, protons and light ions.

When analysing the factors affecting the relative biological effectiveness (RBE) of different radiation qualities, it is essential to consider particularly the low-energy slowing-down electrons (around 100 eV to 1 keV) since they have the potential of inflicting severe damage to the DNA. We present a modified and extended version of the Monte Carlo code PENELOPE that enables scoring of slowing-down spectra. mean local energy imparted spectra and average intra-track nearest-neighbour energy deposition distances of the secondary electrons generated by different radiation qualities, such as electrons, photons, protons and light ions in general. The resulting spectra show that the low-linear energy transfer (LET) beams, 60Co gamma-rays and electrons with initial energies of 0.1 MeV and higher, have as expected approximately the same electron slowing-down fluence per unit dose in the biologically important low-energy interval. Consistent with the general behaviour of the RBE of low-energy electrons, protons and light ions, the low-energy electron slowing-down fluence per unit dose is larger than for low-LET beams, and it increases with decreasing initial projectile energy.

Silicon diodes as detectors for backscatter radiation in photon fields.

We investigated the use of unencapsulated silicon semiconductor detectors for backscatter radiation detection. The results were compared with Monte Carlo (MC) calculations modelling the experimental set-up. A special diode was manufactured, which was designed so that it allowed the positioning of different materials in close contact with the detector surface. Polymethylmethacrylate (PMMA), Pb, Ti and Fe (stainless steel) were used as backscatter materials. The diode signal was measured by integrating the current when irradiating the diode with an equal photon fluence obtained from a medical Co-60 source. When compared to the signal with PMMA as backscatter material the increase in signal was 21%, 27% and 73% for Ti, Fe and Pb, respectively. This is in reasonable agreement with the MC calculations, when taking the effective measurement depth in the Si diode detector into account.

General characteristics of the use of silicon diode detectors for clinical dosimetry in proton beams.

The properties of silicon diode detectors, used for dosimetry in clinical proton beams, were investigated with special regard to the measurement of relative dose distributions in water. Different types of silicon diode detector were studied, and the resulting distributions of detector signal versus depth in the water phantom were compared with the corresponding distributions obtained with a plane-parallel NACP ionization chamber. The measurements were performed in a proton beam with an initial energy of 173 MeV. It is shown that the Hi-p silicon detector gives a signal which is proportional to the ionization density in the silicon crystal in all parts of the Bragg curve, and for all levels of accumulated dose to the detector. This is in contrast to detectors based on n-type silicon, or on low resistivity p-type silicon. After pre-irradiation, these latter detectors show a stopping-power dependent recombination, yielding an increase in the detector signal per unit dose with increasing LET. This effect leads to an over-response in the Bragg peak, which increases gradually with the accumulated detector dose. Using the Hi-p silicon diode detector, the depth ionization distribution was found to be equal to the distribution obtained with the plane-parallel NACP ionization chamber at all pre-irradiation levels, within the experimental accuracy. This implies that the quotient between the ionization in the detector and the absorbed dose to the surrounding water is equal for these detectors.

Development of a compact proton scanning system in Uppsala with a moveable second magnet.

A scanned proton beam yields dose distributions that in most cases are superior to passively scattered proton beams and to other external radiation treatment modalities. The present paper gives a description of the scanning system that has been developed at the Svedberg Laboratory (TSL) in Uppsala. The scanning technique and the technical design are described. The solution with a small pole gap of the magnets and a moveable second magnet results in a very compact scanning head, which can therefore be incorporated in a gantry of relatively limited size. A prototype was constructed that has been used to realize various dose distributions with a scanned beam of 180 MeV protons at TSL.

Implementation of pencil kernel and depth penetration algorithms for treatment planning of proton beams.

The implementation of two algorithms for calculating dose distributions for radiation therapy treatment planning of intermediate energy proton beams is described. A pencil kernel algorithm and a depth penetration algorithm have been incorporated into a commercial three dimensional treatment planning system (Helax-TMS, Helax AB, Sweden) to allow conformal planning techniques using irregularly shaped fields, proton range modulation, range modification and dose calculation for non-coplanar beams. The pencil kernel algorithm is developed from the Fermi Eyges formalism and Molière multiple-scattering theory with range straggling corrections applied. The depth penetration algorithm is based on the energy loss in the continuous slowing down approximation with simple correction factors applied to the beam penumbra region and has been implemented for fast, interactive treatment planning. Modelling of the effects of air gaps and range modifying device thickness and position are implicit to both algorithms. Measured and calculated dose values are compared for a therapeutic proton beam in both homogeneous and heterogeneous phantoms of varying complexity. Both algorithms model the beam penumbra as a function of depth in a homogeneous phantom with acceptable accuracy. Results show that the pencil kernel algorithm is required for modelling the dose perturbation effects from scattering in heterogeneous media.

Stereotactic irradiation of skull base meningiomas with high energy protons.

Nineteen patients with inextirpable skull base meningioma with involvement of neurovascular structures were given irradiation with a 180 MeV proton beam at the The Svedberg Laboratory, Uppsala, Sweden. The patients were treated seated in a fixed position with a stereotactic approach. Titanium-markers to the outer table served for identification and verification of the target positioning for dose planning and irradiation. The patients were given a total dose of 24 Gy in four consecutive daily 6 Gy fractions. All patients have been followed for at least 36 months. So far no meningiomas have progressed after treatment. Two patients have developed corticosteroid responsive oedema in the target area 6 moths after treatment. Late, but not serious, symptoms of side effects have been observed in one patient.

Ferrous sulphate gel dosimetry and MRI for proton beam dose measurements.

Ferrous sulphate gel dosimetry has the potential for measurement of absorbed dose distributions in proton therapy. The chemical properties of the gel are altered according to the radiation dose and these changes can be evaluated in three dimensions using MRI. The purpose of this work was to investigate the properties of a ferrous gel used with clinical proton beams. The gel was irradiated with both monoenergetic and range-modulated proton beams. It was then evaluated using MRI. The depth dose by means of the 1/T1 distribution was studied and compared with data from a plane-parallel plate ionization chamber. 1/T1 was shown to be proportional to the dose at a mean proton energy of approximately 90 MeV. The dose response was no different from that obtained using photon beams. However, on normalization at the entrance, the relative 1/T1 at the Bragg peak was 15-20% lower than the corresponding ionization chamber data for the monoenergetic proton beam. Better agreement was found for the modulated beam, but with significant differences close to the distal edge of the 1/T1 distribution. The change in sensitivity with depth was explained by means of a linear energy transfer dependence. This property was further studied using Monte Carlo methods.

Proton dosimetry intercomparison based on the ICRU report 59 protocol.

BACKGROUND AND PURPOSE: A new protocol for calibration of proton beams was established by the ICRU in report 59 on proton dosimetry. In this paper we report the results of an international proton dosimetry intercomparison, which was held at Loma Linda University Medical Center. The goals of the intercomparison were, first, to estimate the level of consistency in absorbed dose delivered to patients if proton beams at various clinics were calibrated with the new ICRU protocol, and second, to evaluate the differences in absorbed dose determination due to differences in 60Co-based ionization chamber calibration factors. MATERIALS AND METHODS: Eleven institutions participated in the intercomparison. Measurements were performed in a polystyrene phantom at a depth of 10.27 cm water equivalent thickness in a 6-cm modulated proton beam with an accelerator energy of 155 MeV and an incident energy of approximately 135 MeV. Most participants used ionization chambers calibrated in terms of exposure or air kerma. Four ionization chambers had 60Co-based calibration in terms of absorbed dose-to-water. Two chambers were calibrated in a 60Co beam at the NIST both in terms of air kerma and absorbed dose-to-water to provide a comparison of ionization chambers with different calibrations. RESULTS: The intercomparison showed that use of the ICRU report 59 protocol would result in absorbed doses being delivered to patients at their participating institutions to within +/-0.9% (one standard deviation). The maximum difference between doses determined by the participants was found to be 2.9%. Differences between proton doses derived from the measurements with ionization chambers with N(K)-, or N(W) - calibration type depended on chamber type. CONCLUSIONS: Using ionization chambers with 60Co calibration factors traceable to standard laboratories and the ICRU report 59 protocol, a distribution of stated proton absorbed dose is achieved with a difference less than 3%. The ICRU protocol should be adopted for clinical proton beam calibration. A comparison of proton doses derived from measurements with different chambers indicates that the difference in results cannot be explained only by differences in 60Co calibration factors.

Potential gains using high-energy protons for therapy of malignant tumours.

High-energy protons have physical properties that virtually always will result in geometrically better dose distributions than can be achieved using photons or electrons. The clinical gains in terms of the probability of higher tumour control and/or the reduced probability of normal tissue complications are, however, not completely known. Comparative model dose planning studies using real patients offer the possibility of estimating the potential gains using a new technique. Several recently completed model studies, including clinically relevant endpoints, indicate that protons may have advantages, even when compared with the conventional treatment that is likely to be introduced at the most advanced hospitals world-wide within the next decade. These advantages can be seen not only in well-demarcated targets close to risk organs, but also when irradiating extended irregular tissue volumes at risk of containing tumour cells.

Comparative treatment planning between proton and x-ray therapy in esophageal cancer.

PURPOSE: Conformal treatment planning with megavoltage x-rays and protons for five patients with esophageal cancer has been studied in an attempt to determine if there are advantages of using protons instead of x-rays. METHODS AND MATERIALS: For each of the five patients, two different proton plans, one x-ray plan, and one mixed plan with x-rays and protons were made. A three-dimensional treatment planning system, TMS, was used. The evaluation of the different plans was made by applying the tumor control probability (TCP) model proposed by Nahum and Webb and the normal tissue complication (NTCP) model proposed by Lyman on the dose distributions in terms of dose-volume histograms (DVHs). RESULTS: The comparison shows advantages of using protons instead of x-rays for all five patients. The dose-limiting organs at risk are the spinal cord, the lungs, and the heart, but the proton plans also spare the kidneys better than the x-ray plan does. At 5% NTCP in any risk organ, the calculated mean TCP value for the five patients is increased by an average of 20%-units (from 2 to 23%-units) with the best proton plan compared with x-rays only. However, if we assume maximally a 1% risk in the spinal cord and a total NTCP for the two lungs of 100%, the mean TCP value for the five patients is increased from 6 to 49% with the best proton plan compared with x-rays only. The corresponding figure for the mixed plan is 27%. These gains are relatively insensitive to variations within reasonable limits in the biological parameters. CONCLUSIONS: Protons appear to have clear therapeutic advantages over conventional external radiotherapy when treating esophageal carcinoma.

Fast 2D phantom dosimetry for scanning proton beams.

A quality control system especially designed for dosimetry in scanning proton beams has been designed and tested. The system consists of a scintillating screen (Gd2O2S:Tb), mounted at the beam-exit side of a phantom, and observed by a low noise CCD camera with a long integration time. The purpose of the instrument is to make a fast and accurate two-dimensional image of the dose distribution at the screen position in the phantom. The linearity of the signal with the dose, the noise in the signal, the influence of the ionization density on the signal, and the influence of the field size on the signal have been investigated. The spatial resolution is 1.3 mm (1 s.d.), which is sufficiently smaller than typical penumbras in dose distributions. The measured yield depends linearly on the dose and agrees within 5% with the calculations. In the images a signal to noise ration (signal/1 s.d.) of 10(2) has been found, which is in the same order of magnitude as expected from the calculations. At locations in the dose distribution possessing a strong contribution of high ionization densities (i.e., in the Bragg peak), we found some quenching of the light output, which can be described well by existing models if the beam characteristics are known. For clinically used beam characteristics such as a Spread Out Bragg peak, there is at most 8% deviation from the NACP ionization chamber measurements. The conclusion is that this instrument is a useful tool for quick and reliable quality control of proton beams. The long integration-time capabilities of the system make it worthwhile to investigate its applicability in scanning proton beams and other dynamic treatment modalities.

Rejoining of DNA double-strand breaks induced by accelerated nitrogen ions.

Rejoining of radiation-induced DNA double-strand breaks (dsb) was measured in cultured cells with pulsed-field gel electrophoresis after radiation doses in the range of 5-30 Gy. Human glioma, U-343MG and Chinese hamster, V79, cells were irradiated with either accelerated nitrogen ions of high linear energy transfer, LET approximately 125 keV/ microns, or photons from 60Co. The induction frequencies of dsb were similar for the two radiation qualities with a relative biological effectiveness, RBE, of 0.90 and 0.89 for the human and hamster cell lines respectively. The biphasic rejoining kinetics differed significantly between the two radiation qualities when studied in the human glioma cells. The difference was seen within the first hour after irradiation and after 6 h there were considerable differences in both the total amount of unrejoined dsb and the fraction of dsb rejoined during the slow phase. When rejoining was analysed 20-22 h after irradiation, the nitrogen ions gave 2.5-2.9 times more residual dsb than the gamma photons. The results for the hamster V79 cells were, up to 2h after irradiation, similar, but the difference between the two radiation qualities was less accentuated. In summary, similar initial yields of dsb after exposure of cells to high or low LET resulted in both radiation quality and cell type-dependent differences when the rejoining of these breaks were compared.

Faraday cup dosimetry in a proton therapy beam without collimation.

A Faraday cup in a proton beam can give an accurate measurement of the number of protons collected by the cup. It is shown that the collection efficiency with a proper design can be close to unity. To be able to calibrate an ionization chamber from such a measurement, as is recommended in some dosimetry protocols, the energy spectrum of the proton beam must be accurately known. This is normally not the case when the lateral beam extension is defined by collimators. Therefore a method for relating an ionization chamber measurement in an uncollimated beam to the total number of protons in the beam has been developed and is described together with experimental results from calibrating an ionization chamber using this method in the therapeutic beam in Uppsala. This method is applicable to ionization chambers of any shape and the accuracy is estimated to be 1.6% (1 SD).

Ionization chamber dosimetry of proton beams using cylindrical and plane parallel chambers. Nw versus Nk ion chamber calibrations.

Determinations of the absorbed dose in a 170 MeV proton beam have been performed using seven ionization chambers of different types: five cylindrical (two FWT IC-18 and three NE-2571, of which one was modified to have the central electrode made of graphite) and two plane parallel (NACP-02 and Roos FK-6). The ionization was converted into absorbed dose in the proton beam according to the generalization of the formalism provided by the IAEA Code of Practice (TRS 277), which enables the use of the same equations for all kinds of beam used in radiotherapy. The absorbed dose obtained with the two IC-18 chambers, a chamber type commonly used as a reference in proton beams, was up to 1.5% lower than that obtained with the Farmer NE-2571 chamber, which was used as the reference in this work when calibration factors in terms of NK were used. To investigate this difference, experimental ND factors for six chambers (the two IC-18 chambers, the NACP-02, the FK-6 and two of the NE-2571 chambers) were determined in a high-energy electron beam. The procedure commonly recommended for plane parallel ion chambers was used for all the chambers, using the same reference chamber, a Farmer NE-2571. In the 170 MeV proton beam all the ND factors yielded consistent absorbed dose determinations within the estimated experimental uncertainties. This finding calls into question the value of the product kattkm for the IC-18 chamber given by the IAEA Code of Practice used in this comparison, and points at possible chamber to chamber variations that theoretical kattkm factors cannot predict. The investigations enabled the determination of the Pwall(60Co) factor of the Roos FK-6 plane parallel chamber, yielding 1.003 +/- 0.5%, and a correction for the effect of the aluminium central electrode of NE-2571 chambers in proton beams, equal to 1.003 +/- 0.4%. Two of the chambers (the plane parallel FK-6 and the modified cylindrical NE-2571) were provided with calibration factors in terms of absorbed dose to water, Nw, at the quality of 60Co by the Primary Standard Dosimetry Laboratory in Germany (PTB). Using the Nw formalism excellent agreement was found with the determination based on the experimental ND, giving support to the implementation of the NW procedure in therapeutic proton beams.

Dose calculations in proton beams: range straggling corrections and energy scaling.

Three-dimensional dose planning systems employing accurate proton transport algorithms are essential for calculating absorbed dose distributions in proton therapy. In this paper, a pencil beam algorithm for the transport of protons in materials of interest for radiation therapy is developed. The Fermi-Eyges multiple-scattering theory is used to derive transport equations for calculating proton fluence and absorbed dose distributions. The multiple-scattering theory of Molière is used to predict mean square scattering angles and to develop an expression for calculating the root mean square (RMS) radial spread of a proton pencil beam, as a function of depth, in an arbitrary scattering material. A correction factor is suggested to account for the decrease in the radial spread at the end of the range due to range straggling. The effects of neglecting large-angle scattering events and the possibility of incorporating such events into the pencil beam algorithm are discussed. An energy scaling technique for determining the water-equivalent surface energy at a given depth in a heterogeneous scattering medium is developed. The water-equivalent energy, giving the same Molière scattering parameter B in water, is determined and the 1/e angle in water is scaled to the appropriate width in the scattering material. By using stored analytically or Monte Carlo calculated pencil beam distributions in water, the large-angle single-scattering events may be incorporated by approximating the scattering in an arbitrary material by the scattering in water for protons of the appropriate water-equivalent surface energy.

Cell type dependent effectiveness of tumour cell inactivation by radiation with increased ionisation density.

Radiation with increased ionization density, LET, will in the near future be applied in targeted radiotherapy and has already, to some degree, been applied in external radiotherapy with accelerated ions. There are indications from the literature that different types of cells are sensitized differently when the LET is increased. Radiation with three different ionisation densities was applied in the present study; 0.8 keV/microns photons from a reference 60Co source, 6 keV/microns helium ions from the entrance region of a monoenergetic helium ion beam and 25 keV/microns from a range modulated helium beam. Three types of cultured cells were analysed: human colon carcinoma LS-174T, human glioma U-343MG and hamster embryonic lung V79-379A. There were interesting differences between the cell types; the LS-174T cells showed strong sensitization already at an LET of 6 keV/microns and there was nearly no difference between the shape of the survival curves after irradiation with 6 or 25 keV/microns. The V79-379A cells were less sensitive to the 6 keV/microns radiation quality and the survival curve was, in this case, very similar to the reference 60Co survival curve. However, the V79-379A cells were sensitized when exposed to the 25 keV/microns helium ions. The U-343MG cells were intermediate in the sense that the 6 keV/microns curve fell in between the 60Co and the 25 keV/microns curves. These variations indicate that different types of cells react differently to changes in LET and that this is probably of special interest for intermediate LET radiation. Some cells might be easily sensitized by intermediate LET qualities while others might be more resistant and this is of importance for the future optimization of radiation treatment with both targeted agents and accelerated ions.