Validation of dose painting of lung tumours using alanine/EPR dosimetry.

Biologic image guided radiotherapy (RT) with escalated doses to tumour sub volumes challenges today's RT dose planning and delivery systems. In this phantom study, we verify the capability of a clinical dose planning and delivery system to deliver an 18F-FDG-PET based dose painted treatment plan to a lung tumour. Furthermore, we estimate the uncertainties of the dose painted treatment compared to conventional RT plans. An anthropomorphic thorax phantom of polystyrene and polyurethane was constructed based on CT images of a lung cancer patient. 101 EPR/alanine dosimeters were placed in separate cavities within the phantom. IMRT and VMAT plans were generated in Eclipse (version 10.0, Analytical Anisotropic Algorithm version 10.2.28, Varian Medical Systems, Inc.) for 6 and 15 MV photons, based on 18F-FDG-PET/CT images of the patient. A boost dose of 3.8 Gy/fraction was given to the 18F-FDG-avid region (biological planning volume; BTV), whereas 3.1 Gy/fraction was planned to the planning target volume (PTV, excluding the BTV). For the homogenous plans, 3.2 Gy/fraction was given to the PTV. Irradiation of the phantom was carried out at a Varian Trilogy linear accelerator (Varian Medical Systems, Inc.). Uncertainties involved in treatment planning and delivery were estimated from portal dosimetry gamma evaluation. Measured and calculated doses were compared by Bland-Altmann analysis. For all treatment plans, all dose-volume objectives could be achieved in the treatment planning system. The mean absolute differences between calculated and measured doses were small (<0.1 Gy) for BTV, PTV-BTV, lung and soft tissue. The estimated uncertainty of the planned doses was less than 3% for all plans, whereas the estimated uncertainty in the measured doses was less 2.3%. Our results show that planning and delivery of dose escalated lung cancer treatment on a clinical dose planning and delivery system has high dosimetric accuracy. The uncertainties associated with the dose escalated treatment plans are comparable to the conventional plans.

Lithium Formate for EPR Dosimetry (2): Secondary Radicals in X-Irradiated Crystals.

The secondary radiation-induced radicals in lithium formate monohydrate were studied using electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR) and ENDOR-induced EPR (EIE) techniques complemented with periodic density functional theory (DFT) calculations. Single crystals of lithium formate monohydrate were X irradiated at 77 K and at room temperature. The main radicals present after irradiation at 77 K are the CO(2)(•-) radical (R1), the recently identified protonated electron-gain product, HCOOH(•-) (R2) (Krivokapic et al., Radiat Res 2014: 181:503-11), and a different geometrical conformation of this latter radical, a species that, up until now, has remained unidentified (R3). The successful quantum chemical modeling of R3 confirmed its structure and also provided a possible mechanism for its formation. After irradiation at 295 K, the crystals were investigated both shortly after irradiation and after storage for eight months at room temperature in ambient environments. After long-term storage the CO(2)(•-) radical had significantly decayed and the EPR spectra were dominated by two minority radicals. Both of these radicals are most likely formate-centered π-radicals, and based on the observed EPR parameters (g- and hyperfine coupling tensors) tentative candidates are the CO(•-) radical and the dimer formed by the CO(2)(•-) radical and a neighboring formate molecule yielding the radical (-)O(2)C·O·(•)CH·O(-).

Lithium formate for EPR dosimetry: radiation-induced radical trapping at low temperatures.

Radiation-induced primary radicals in lithium formate. A material used in EPR dosimetry have been studied using electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR) and ENDOR-Induced EPR (EIE) techniques. In this study, single crystals were X irradiated at 6-8 K and radical formation at these and higher temperatures were investigated. Periodic density functional theory calculations were used to assist in assigning the radical structures. Mainly two radicals are present at 6 K, the well-known CO2(•-) radical and a protonated electron-gain product. Hyperfine coupling tensors for proton and lithium interactions were obtained for these two radicals and show that the latter radical exists in four conformations with various degrees of bending at the radical center. Pairs of CO2(•-) radicals were also observed and the tensor for the electron-electron dipolar coupling was determined for the strongest coupled pair, which exhibited the largest spectral intensity. Upon warming, both the radical pairs and the reduction product decay, the latter apparently by a transient species. Above 200 K the EPR spectrum was mainly due to the CO2(•-) (mono) radicals, which were previously characterized as the dominant species present at room temperature and which account for the dosimetric EPR signal.

The risk of radiation-induced breast cancers due to biennial mammographic screening in women aged 50-69 years is minimal.

BACKGROUND: The main aim of mammographic screening is to reduce the mortality from breast cancer. However, use of ionizing radiation is considered a potential harm due to the possible risk of inducing cancer in healthy women. PURPOSE: To estimate the potential number of radiation-induced breast cancers, radiation-induced breast cancer deaths, and lives saved due to implementation of organized mammographic screening as performed in Norway. MATERIAL AND METHODS: We used a previously published excess absolute risk model which assumes a linear no-threshold dose-response. The estimates were calculated for 100,000 women aged 50-69 years, a screening interval of 2 years, and with an assumed follow-up until the age of 85 or 105 years. Radiation doses of 0.7, 2.5, and 5.7 mGy per screening examination, a latency time of 5 or 10 years, and a dose and dose-rate effectiveness factor (DDREF) of 1 or 2 were applied. RESULTS: The total lifetime risk of radiation-induced breast cancers per 100,000 women was 10 (95% CI: 4-25) if the women were followed from the ages of 50 to 85 years, for a dose of 2.5 mGy, a latency time of 10 years, and a DDREF of 1. For the same parameter values the number of radiation-induced breast cancer death was 1 (95% CI: 0-2). The assumed number of lives saved is approximately 350. CONCLUSION: The risk of radiation-induced breast cancer and breast cancer death due to mammographic screening is minimal. Women should not be discouraged from attending screening due to fear of radiation-induced breast cancer death.

Radiation products at 77 K in trehalose single crystals: EMR and DFT analysis.

The radicals obtained in trehalose dihydrate single crystals after 77 K X-irradiation have been investigated at the same temperature using X-band electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR), and ENDOR-induced EPR (EIE) techniques. Five proton hyperfine coupling tensors were unambiguously determined from the ENDOR measurements and assigned to three carbon-centered radical species (T1, T1*, and T2) based on the EIE spectra. EPR angular variations revealed the presence of four additional alkoxy radical species (T3 to T6) and allowed determination of their g tensors. Using periodic density functional theory (DFT) calculations, T1/T1*, T2, and T3 were identified as H-loss species centered at C4, C1', and O2', respectively. The T4 radical is proposed to have the unpaired electron at O4, but considerable discrepancies between experimental and calculated HFC values indicate it is not simply the (net) H-loss species. No suitable models were found for T5 and T6. These exhibit a markedly larger g anisotropy than T3 and T4, which were not reproduced by any of our DFT calculations.

The energy dependence of lithium formate and alanine EPR dosimeters for medium energy x rays.

PURPOSE: To perform a systematic investigation of the energy dependence of alanine and lilthium formate EPR dosimeters for medium energy x rays. METHODS: Lithium formate and alanine EPR dosimeters were exposed to eight different x-ray beam qualities, with nominal potentials ranging from 50 to 200 kV. Following ionometry based on standards of absorbed dose to water, the dosimeters were given two different doses of approximately 3 and 6 Gy for each radiation quality, with three dosimeters for each dose. A reference series was also irradiated to three different dose levels at a 60Co unit. The dose to water energy response, that is, the dosimeter reading per absorbed dose to water relative to that for 60Co gamma-rays, was estimated for each beam quality. In addition, the energy response was calculated by Monte Carlo simulations and compared to the experimental energy response. RESULTS: The experimental energy response estimates ranged from 0.89 to 0.94 and from 0.68 to 0.90 for lithium formate and alanine, respectively. The uncertainties in the experimental energy response estimates were typically 3%. The relative effectiveness, that is, the ratio of the experimental energy response to that following Monte Carlo simulations was, on average, 0.96 and 0.94 for lithium formate and alanine, respectively. CONCLUSIONS: This work shows that lithium formate dosimeters are less dependent on x-ray energy than alanine. Furthermore, as the relative effectiveness for both lithium formate and alanine were systematically less than unity, the yield of radiation-induced radicals is decreased following x-irradiation compared to irradiation with 60Co y-rays.

Interphantom and interscanner variations for Hounsfield units--establishment of reference values for HU in a commercial QA phantom.

In computer tomography (CT) diagnostics, the measured Hounsfield units (HU) are used to characterize tissue and are in that respect compared to nominal HU values found in the radiological literature. Quality assurance (QA) phantoms are commercially available with a variety of tissue substitutes and materials to test the HU values in CT. It is however recognized from CT physics that the HU for a given material is energy dependent and may vary substantially between scanners. The aim of this study is to analyze the characteristics of a commonly used QA phantom, the Catphan 500/600 (The Phantom Laboratory, NY). Four CT phantoms were scanned on one CT scanner to examine possible interphantom variations in HU values. Secondly, one selected phantom was scanned at three kVp levels on eight different CT scanners. The interphantom variations in HU values were small, in the range 2-5 HU. The interscanner variations were however substantial, in the range 7-56 HU depending on energy and material. Varying the x-ray energy produced a shift in the measured HU of up to 79 HU on one scanner. Reference HU values for the eight sensitometric test materials in Catphan are provided for eight CT scanner models from four vendors. The reference HU values are provided for 80, 120 and 140 kVp. Our results suggest that scanner-independent threshold levels for HU should be used only with extreme caution. Tissue characterization can be used provided that a scanner-specific data set for normal and abnormal is determined.

Radical formation in lithium formate EPR dosimeters after irradiation with protons and nitrogen ions.

Radical formation in polycrystalline lithium formate monohydrate after irradiation with gamma rays, protons and nitrogen ions at room temperature was studied by continuous-wave electron paramagnetic resonance (EPR) spectroscopy. The linear energy transfer (LET) of the various radiation beams was 0.2, 0.7-3.9 and 110-164 keV/microm for gamma rays, protons and nitrogen ions, respectively. Doses between 5 and 20 Gy were given. The EPR reading (the area under the EPR absorption resonance) increased linearly with dose for all types of radiation. As the LET increased, the relative effectiveness (the EPR reading per dose relative to that for gamma rays) decreased, while the EPR line width increased. Track structure theory and modeling of detector effectiveness predicted the dosimeter response observed after proton and nitrogen-ion irradiation. A semi-empirical line broadening model including dipolar spin-spin interactions was developed that explained the dependence of the line width on LET. The findings indicate that the local radical density in lithium formate is increased after high-LET irradiation.

Dosimetry of stereotactic radiosurgery using lithium formate EPR dosimeters.

Small lithium formate EPR (electron paramagnetic resonance) dosimeters (diameter 3 mm, height 2 mm) were produced and employed for 2D dosimetry of stereotactic radiosurgery (SRS). An anthropomorphic head phantom with an in-house made insert holding 45 lithium formate dosimeters was used. A spherical target was outlined centrally in planning CT images of the head and an SRS dose plan with three arcs was made using the iPlan planning system. Beam collimation was achieved with the BrainLAB m3 micro-MLC. The minimum target dose was 15 Gy. The planned dose distribution was compared to measurements. For dosimetry, a dosimeter calibration series was generated with doses from 1 to 20 Gy. At the treatment unit, three replicate measurement series were performed. The measurements gave on average 2.2% lower dose at the plateau of the dose distribution compared to the dose plan. Larger differences were seen in the penumbra, where the dose plan underestimated the dose gradients. By repeated measurements, the systematic and random error in the SRS delivery was estimated to less than 1 mm. In conclusion, the planning system produced an intracranial dose distribution with tolerable accuracy. Furthermore, small lithium formate EPR dosimeters were useful for measuring SRS dose distributions.

The energy dependence of lithium formate EPR dosimeters for clinical electron beams.

The objective of this study was to investigate the potential of using polycrystalline lithium formate for EPR (electron paramagnetic resonance) dosimetry of clinical electron beams, with the main focus on the dose-to-water energy response. Lithium formate dosimeters were irradiated using (60)Co gamma-rays and 6-20 MeV electrons in a PMMA phantom to doses in the range of 3-9 Gy. A plane-parallel ion chamber was used for water-based absolute dosimetry. In addition, the electron/photon transport was simulated using the EGSnrc Monte Carlo code. From the EPR measurements, the standard deviation of single dosimeter readings was 1.2%. The experimental energy response (the lithium formate dosimeter reading per absorbed dose to water for electrons relative to that for (60)Co gamma rays) was nearly independent of the electron energy and on average 0.99 +/- 0.03. The Monte Carlo calculated energy response was on average 0.5% higher than the experimental energy response, the difference being not significant. Simulations with water and polystyrene as irradiation media indicated that the energy response of lithium formate dosimeters was nearly independent of the phantom materials. In conclusion, lithium formate EPR dosimetry of clinical electron beams provides precise dose measurements with low dependence on the electron energy.

EPR dosimetry of radiotherapy photon beams in inhomogeneous media using alanine films.

In the current work, EPR (electron paramagnetic resonance) dosimetry using alanine films (134 microm thick) was utilized for dose measurements in inhomogeneous phantoms irradiated with radiotherapy photon beams. The main phantom material was PMMA, while either Styrofoam or aluminium was introduced as an inhomogeneity. The phantoms were irradiated to a maximum dose of about 30 Gy with 6 or 15 MV photons. The performance of the alanine film dosimeters was investigated and compared to results from ion chamber dosimetry, Monte Carlo simulations and radiotherapy treatment planning calculations. It was found that the alanine film dosimeters had a linear dose response above approximately 5 Gy, while a background signal obscured the response at lower dose levels. For doses between 5 and 60 Gy, the standard deviation of single alanine film dose estimates was about 2%. The alanine film dose estimates yielded results comparable to those from the Monte Carlo simulations and the ion chamber measurements, with absolute differences between estimates in the order of 1-15%. The treatment planning calculations exhibited limited applicability. The current work shows that alanine film dosimetry is a method suitable for estimating radiotherapeutical doses and for dose measurements in inhomogeneous media.

Single crystals of L-O-serine phosphate X-irradiated at low temperatures: EPR, ENDOR, EIE, and DFT studies.

Single crystals of the phosphorylated amino acid L-O-serine phosphate were X-irradiated and studied at 10 K and at 77 K using EPR, ENDOR, and EIE techniques. Two radicals, R1(10 K) and R1(77 K), were detected and characterized as two different geometrical conformations of the protonated reduction product >CH-C(OH)(2). R1(10 K) is only observed after irradiation at 10 K, and upon heating to 40 K, R1(10 K) transforms rapidly and irreversibly into R1(77 K). The transition from R1(10 K) to R1(77 K) strongly increases the isotropic hyperfine coupling of the C-CH(beta) coupling (Delta = 32 MHz) and the major C-OH(beta) coupling (Delta = 47 MHz), in sharp contrast to the their much reduced anisotropic hyperfine couplings after the transition. An umbrella-like inversion of the carboxylic acid center, accompanied by minor geometrical adjustments, explains the changes of these observed isotropic and anisotropic couplings. DFT calculations were done on the reduced and protonated L-O-serine phosphate radical at the B3LYP/6-311+G(2df,p)//B3LYP/6-31+G(d) level of theory in order to support the experimental observations. Two different conformations of the anion radical, related by an inversion at the carboxylic center, could be found within the single molecule partial energy-optimization scheme. These two conformations reproduce the experimental hyperfine couplings from radicals R1(10 K) and R1(77 K). A third radical, radical R2, was observed experimentally at both 10 and 77 K and was shown to be due to the decarboxylated L-O-serine phosphate oxidation product, a conclusion fully supported from the DFT calculations. Upon thermal annealing from 77 to 295 K, radicals R1(77 K) and R2 disappeared and all three previously observed room-temperature radicals could be observed. No phosphate-centered radicals could be observed at any temperatures, indicating that the phosphate-ester bond break for one of the room-temperature radicals does not occur by dissociative electron capture at the phosphate group.

LET effects following neutron irradiation of lithium formate EPR dosimeters.

Lithium formate electron paramagnetic resonance (EPR) dosimeters were irradiated using 60Co gamma-rays or fast neutrons to doses ranging from 5 to 20 Gy and investigated by EPR spectroscopy. Using a polynomial fitting procedure in order to accurately analyze peak-to-peak line widths of first derivative EPR spectra, dosimeters irradiated with neutrons had on average 4.4+/-0.9% broader EPR resonance lines than gamma-irradiated dosimeters. The increase in line width was slightly asymmetrical. Computer simulated first derivative polycrystalline EPR spectra of a *CO2- radical gave very good reconstructions of experimental spectra of irradiated dosimeters. The spectrum simulations could then be used as a tool to investigate the line broadening observed following neutron irradiation. It was shown that an increase in the simulated Lorentzian line width could explain both the observed line broadening and the asymmetrical effect. The ratio of the peak-to-peak amplitude of first derivative EPR spectra obtained at two different microwave powers (20 and 0.5 mW) was 7.8+/-1.2% higher for dosimeters irradiated with neutrons. The dependence of the spectrum amplitude on the microwave power was extensively investigated by fitting observations to an analytical non-linear model incorporating, among others, the spin-lattice (T1) and spin-spin (T2) relaxation times as fitting parameters. Neutron irradiation resulted in a reduction in T(2) in comparison with gamma-irradiation, while a smaller difference in T1 was found. The effects observed indicate increased local radical density following irradiation using high linear energy transfer (LET) neutrons as compared to low LET gamma-irradiation. A fingerprint of the LET may thus be found either by an analysis of the line width or of the dependence of the spectrum amplitude on the microwave power. Lithium formate is therefore a promising material for EPR dosimetry of high LET radiation.

Electron paramagnetic resonance (EPR) dosimetry using lithium formate in radiotherapy: comparison with thermoluminescence (TL) dosimetry using lithium fluoride rods.

Solid-state radiation dosimetry by electron paramagnetic resonance (EPR) spectroscopy and thermoluminescence (TL) was utilized for the determination of absorbed doses in the range of 0.5-2.5 Gy. The dosimeter materials used were lithium formate and lithium fluoride (TLD-100 rods) for EPR dosimetry and TL dosimetry, respectively. 60Co gamma-rays and 4, 6, 10 and 15 MV x-rays were employed. The main objectives were to compare the variation in dosimeter reading of the respective dosimetry systems and to determine the photon energy dependence of the two dosimeter materials. The EPR dosimeter sensitivity was constant over the dose range in question, while the TL sensitivity increased by more than 5% from 0.5 to 2.5 Gy, thus displaying a supralinear dose response. The average relative standard deviation in the dosimeter reading per dose was 3.0% and 1.2% for the EPR and TL procedures, respectively. For EPR dosimeters, the relative standard deviation declined significantly from 4.3% to 1.1% over the dose range in question. The dose-to-water energy response for the megavoltage x-ray beams relative to 60Co gamma-rays was in the range of 0.990-0.979 and 0.984-0.962 for lithium formate and lithium fluoride, respectively. The results show that EPR dosimetry with lithium formate provides dose estimates with a precision comparable to that of TL dosimetry (using lithium fluoride) for doses above 2 Gy, and that lithium formate is slightly less dependent on megavoltage photon beam energy than lithium fluoride.

Estimation of X-ray beam quality by electron paramagnetic resonance (EPR) spectroscopy.

A novel dosimetry-based technique using EPR spectroscopy to determine X-ray beam quality is proposed. The radiation-sensitive material is made of a mixture of two polycrystalline substances with different X-ray absorption properties. The composite samples, consisting of polycrystalline lithium formate monohydrate and calcium formate, were prepared as pellets, X-irradiated, and analyzed with EPR spectroscopy. The ratio of the EPR signal amplitudes of the two constituents can serve as a measure of the X-ray beam quality given by the equivalent photon energy. The calculation of the signal amplitude ratio involves a reconstruction of the composite EPR spectrum. The logarithm of the signal amplitude ratio appears to be linearly correlated with the logarithm of the equivalent photon energy. The linear relationship can be used as a calibration for estimating the equivalent photon energy from the composite EPR spectrum. The composite material was used to investigate the changes in the equivalent photon energy in a Perspex phantom with increasing depth. When a 220 kV X-ray beam with an equivalent photon energy of about 100 keV was used, changes in the EPR signal amplitude ratio revealed a buildup of scattered photons with increasing depth in the phantom. This change could be related to the equivalent photon energy using the logarithmic calibration curve. It was found that the equivalent photon energy at the depth of 13 cm in the phantom was 25% lower than on its surface. The proposed method can be used for estimating equivalent photon energy in both standardized and non-standardized situations, the latter corresponding to beam setups where use of filters and ionization chambers is difficult or impossible. Also, the system can provide a means for measuring photon energy in X-irradiated phantoms.

EPR dosimetric properties of formates.

As a part of a program to develop an electron paramagnetic resonance (EPR) dosimeter suited for clinical use (doses in the cGy range), polycrystalline samples of lithium formate monohydrate (HCO2Li.H2O), magnesium formate dihydrate (C2H2O4Mg.2H2O), and calcium formate (C2H2O4Ca) have been examined. L-Alanine was included for comparison and reference. Samples were irradiated with 60Co gamma-rays and 60-220 kV X-rays. The dosimeter response was assessed using the peak-to-peak amplitude of the first-derivative EPR spectrum. Dose-response curves for the 60Co gamma-irradiated samples were constructed, and the dependences of the response on the photon energy, microwave power, and modulation amplitude were studied. Stability of the irradiation products upon storage (signal fading) was also investigated. Lithium formate monohydrate is by far the best candidate of the tested formates, suitable for measuring doses down to approximately 0.1 Gy. Lithium formate monohydrate is more sensitive than alanine by a factor of 5.6-6.8 in the tested photon energy range, it exhibits no zero-dose signal and shows a linear dose response in the dose range from 0.2 to 1000 Gy. Its EPR signal was found unchanged in shape and intensity 1 week after irradiation to 10 Gy. Various less favorable properties rendered the other formates generally unsuitable, although calcium formate exhibits some interesting EPR dosimetric properties.

An investigation of the photon energy dependence of the EPR alanine dosimetry system.

The electron paramagnetic resonance (EPR) alanine dosimetry system is based on EPR measurements of radicals formed in alanine by ionizing radiation. The system has been studied to determine its energy dependence for photons in the 10-30 MV region relative to those of 60Co and to find out if the system would be suitable for dosimetry comparisons. The irradiations were carried out at the National Research Council, Ottawa, Canada and the doses ranged from 8 to 54 Gy. The EPR measurements were performed at the University of Oslo, Norway. The ratio of the slope of the alanine reading versus dose-to-water curve for a certain linac photon beam quality and the corresponding slope for a reference 60Co gamma-radiation gives an experimental measure of the relative dose-to-water response of the EPR alanine dosimetry system. For calculating the linear regression coefficients of these alanine reading versus dose curves, the method of weighted least squares was used. This method is assumed to produce more accurate regression coefficients when applied to EPR dosimetry than the common method of standard least squares. The overall uncertainty on the ratio of slopes was between 0.5 and 0.6% for all three linac energies. The relative response for all the linac beams compared to cobalt was less than unity: by about 0.5% for the 20 and 30 MV points but by more than 1% for the 10 MV point. The given standard uncertainties negate concluding that there is any significant internal variation in the measured response as a function of beam quality between the three linac energies. Thus, we calculated the average dose response for all three energies and found that the alanine response is 0.8% (+/-0.5%) lower for high energy x-rays than for 60Co gamma-rays. This result indicates a small energy dependence in the alanine response for the high-energy photons relative to 60Co which may be significant. This result is specific to our dosimetry system (alanine with 20% polyethylene binder pressed into a particular shape) including its waterproofing sleeve of PMMA (2 mm thick); however, we expect that this result may apply to other similar detectors.