Exploring predictive molecules of acute adverse events in response to volumetric­modulated arc therapy for prostate cancer using urinary metabolites.

Volumetric-modulated arc therapy (VMAT) is a radiotherapy technique used to treat patients with localized prostate cancer, which is frequently associated with acute adverse events (AEs) that can affect subsequent treatment. Notably, the radiation dose of VMAT can be tailored to each patient. In the present study, a retrospective analysis was performed to predict acute AEs in response to a therapeutic high radiation dose rate based on urinary metabolomic molecules, which are easily collected as noninvasive biosamples. Urine samples from 11 patients with prostate cancer who were treated with VMAT (76 Gy/38 fractions) were collected. The study found that seven patients (~64%) exhibited genitourinary toxicity (Grade 1) and four patients had no AEs. A total of 630 urinary metabolites were then analyzed using a mass spectrometer (QTRAP6500+; AB SCIEX), and 234 relevant molecules for biological and clinical applications were extracted from the absolute quantified metabolite values using the MetaboINDICATOR tool. In the Grade 1 acute AE group, there was a significant negative correlation (rs=-0.297, P<0.05) between the number of VMAT fractions and total phospholipase A2 activity in the urine. Additionally, patients with Grade 1 AEs exhibited a decrease in PC aa C40:1, a phospholipid. These findings suggested that specific lipids found in urinary metabolites may serve as predictive biomarkers for acute AEs in response to external radiotherapy.

Generality Assessment of a Model Considering Heterogeneous Cancer Cells for Predicting Tumor Control Probability for Stereotactic Body Radiation Therapy Against Non-Small Cell Lung Cancer.

The generality of a model for predicting tumor control probability from in vitro clonogenic survival considering of cancer stem-like cells, the so-called integrated microdosimetric-kinetic model, is presented by comparing the model to public data on stereotactic body radiation therapy for non-small cell lung cancer cells.

Translational study for stereotactic body radiotherapy against non-small cell lung cancer, including oligometastases, considering cancer stem-like cells enable predicting clinical outcome from in vitro data.

BACKGROUND: Curative effects of stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC) have been evaluated using various biophysical models. Because such model parameters are empirically determined based on clinical experience, there is a large gap between in vitro and clinical studies. In this study, considering the heterogeneous cell population, we performed a translational study to realize the possible linkage based on a modeling approach. METHODS: We modeled cell-killing and tumor control probability (TCP) considering two populations: progeny and cancer stem-like cells. The model parameters were determined from in vitro survival data of A549 and EBC-1 cells. Based on the cellular parameters, we predicted TCP and compared it with the corresponding clinical data from 553 patients collected at Hirosaki University Hospital. RESULTS: Using an all-in-one developed model, the so-called integrated microdosimetric-kinetic (IMK) model, we successfully reproduced both in vitro survival after acute irradiation and the 3-year TCP with various fractionation schemes (6-10 Gy per fraction). From the conventional prediction without considering cancer stem cells (CSCs), this study revealed that radioresistant CSCs play a key role in the linkage between in vitro and clinical outcomes. CONCLUSIONS: This modeling study provides a possible generalized biophysical model that enables precise estimation of SBRT worldwide.

The potential failure risk of the cone-beam computed tomography-based planning target volume margin definition for prostate image-guided radiotherapy based on a prospective single-institutional hybrid analysis.

BACKGROUND: The purpose of this study was to evaluate the impact of markerless on-board kilovoltage (kV) cone-beam computed tomography (CBCT)-based positioning uncertainty on determination of the planning target volume (PTV) margin by comparison with kV on-board imaging (OBI) with gold fiducial markers (FMs), and to validate a methodology for the evaluation of PTV margins for markerless kV-CBCT in prostate image-guided radiotherapy (IGRT). METHODS: A total of 1177 pre- and 1177 post-treatment kV-OBI and 1177 pre- and 206 post-treatment kV-CBCT images were analyzed in 25 patients who received prostate IGRT with daily localization by implanted FMs. Intrafractional motion of the prostate was evaluated between each pre- and post-treatment image with these two different techniques. The differences in prostate deviations and intrafractional motions between matching by FM in kV-OBI (OBI-FM) and matching by soft tissues in kV-CBCT (CBCT-ST) were compared by Bland-Altman limits of agreement. Compensated PTV margins were determined and compensated by references. RESULTS: Mean differences between OBI-FM and CBCT-ST in the anterior to posterior (AP), superior to inferior (SI), and left to right (LR) directions were - 0.43 ± 1.45, - 0.09 ± 1.65, and - 0.12 ± 0.80 mm, respectively, with R2 = 0.85, 0.88, and 0.83, respectively. Intrafractional motions obtained from CBCT-ST were 0.00 ± 1.46, 0.02 ± 1.49, and 0.15 ± 0.64 mm, respectively, which were smaller than the results from OBI-FM, with 0.43 ± 1.90, 0.12 ± 1.98, and 0.26 ± 0.80 mm, respectively, with R2 = 0.42, 0.33, and 0.16, respectively. Bland-Altman analysis showed a significant proportional bias. PTV margins of 1.5 mm, 1.4 mm, and 0.9 mm for CBCT-ST were calculated from the values of CBCT-ST, which were also smaller than the values of 3.15 mm, 3.66 mm, and 1.60 mm from OBI-FM. The practical PTV margin for CBCT-ST was compensated with the values from OBI-FM as 4.1 mm, 4.8 mm, and 2.2 mm. CONCLUSIONS: PTV margins calculated from CBCT-ST might be underestimated compared to the true PTV margins. To determine a reliable CBCT-ST-based PTV margin, at least the systemic error Σ and the random error σ for on-line matching errors need to be investigated by supportive preliminary FM evaluation at least once.

Reconsideration of the Iwasaki-Waggener iterative perturbation method for reconstructing high-energy X-ray spectra.

We have reviewed applicable ranges for attenuating media and off-axis distances regarding the high-energy X-ray spectra reconstructed via the Iwasaki-Waggener iterative perturbation method for 4-20 MV X-ray beams. Sets of in-air relative transmission data used for reconstruction of spectra were calculated for low- and high-Z attenuators (acrylic and lead, respectively) by use of a functional spectral formula. More accurate sets of spectra could be reconstructed by dividing the off-axis distances of R = 0-20 cm into two series of R = 0-10 cm and R = 10-20 cm, and by taking into account the radiation attenuation and scatter in the buildup cap of the dosimeter. We also incorporated in the reconstructed spectra an adjustment factor (f (adjust) ≈ 1) that is determined by the attenuating medium, the acceleration voltage, and the set of off-axis distances. This resulted in calculated in-air relative transmission data to within ±2 % deviation for the low-Z attenuators water, acrylic, and aluminum (Al) with 0-50 cm thicknesses and R = 0-20 cm; data to within ±3 % deviation were obtained for high-Z attenuators such as iron (Fe), copper (Cu), silver (Ag), tungsten (W), platinum (Pt), gold (Au), lead (Pb), thorium (Th), and uranium (U) having thicknesses of 0-10 cm and R = 0-20 cm. By taking into account the radiation attenuation and scatter in the buildup cap, we could analyze the in-air chamber response along a line perpendicular to the isocenter axis.

A convolution/superposition method using primary and scatter dose kernels formed for energy bins of X-ray spectra reconstructed as a function of off-axis distance: comparison of calculated and measured 10-MV X-ray doses in thorax-like phantoms.

We performed experimental studies on the convolution/superposition method reported in the former companion paper (Iwasaki in Radiol Phys Technol 4, 2011) using 10-MV X-ray beams from open-jaw-collimated fields. The method uses primary and scatter dose kernels formed for energy bins of X-ray spectra reconstructed as a function of off-axis distance. We made a comparison of calculations and measurements in water phantoms and thorax-like phantoms with respect to percentage depth dose curves, tissue-phantom ratio curves, and dose profiles. We made the dose calculation by taking into account the beam-hardening effect with depth and the off-axis radiation-softening effect. We found that the method could be used, in general, for performing accurate dose calculations.

A convolution/superposition method using primary and scatter dose kernels formed for energy bins of X-ray spectra reconstructed as a function of off-axis distance: a theoretical study on 10-MV X-ray dose calculations in thorax-like phantoms.

A convolution/superposition method is proposed for use with primary and scatter dose kernels formed for energy bins of X-ray spectra reconstructed as a function of off-axis distance. It should be noted that the number of energy bins is usually about ten, and that the reconstructed X-ray spectra can reasonably be applied to media with a wide range of effective Z numbers, ranging from water to lead. The study was carried out for 10-MV X-ray doses in water and thorax-like phantoms with the use of open-jaw-collimated fields. The dose calculations were made separately for primary, scatter, and electron contamination dose components, for which we used two extended radiation sources: one was on the X-ray target and the other on the flattening filter. To calculate the in-air beam intensities at points on the isocenter plane for a given jaw-collimated field, we introduced an in-air output factor (OPF(in-air)) expressed as the product of the off-center jaw-collimator scatter factor (off-center S (c)), the source off-center ratio factor (OCR(source)), and the jaw-collimator radiation reflection factor (RRF(c)). For more accurate dose calculations, we introduce an electron spread fluctuation factor (F (fwd)) to take into account the angular and spatial spread fluctuation for electrons traveling through different media.

[Two approximations to obtain the collimator scatter factor (Sc) for MLC irregular fields].

The collimator scatter factor (S(c)(MLC)) at MLC irregular fields for high-energy X-ray irradiation is generally assumed to be equal to the jaw collimator scatter factor (S(c)(jaw)) of the square field equivalent to the rectangular field produced using pairs of jaw collimators. However, this assumption becomes strained as the ratio of the MLC equivalent square field side to the jaw collimator equivalent square field side decreases. In this study, for 4 MV and 10 MV X-rays, the collimator scatter factor (S(c)(MLC)) for an MLC irregular field could be evaluated with a high degree of accuracy using the MLC irregular correction (F(MIC)) factor or the jaw collimator correction (F(JCC)) factor.

[Method for estimating 4 MV X-ray irregular field dose using the collimator scatter factor (Sc) and phantom scatter factor (Sp)].

Calculation of in-air or in-water dose for 4 MV X-ray irregular fields could be accurately performed using the collimator scatter factor (S(c)) and phantom scatter factor (S(p)) concepts. It has been revealed that the equivalent square field for a multi-leaf collimator (MLC) irregular field can be evaluated accurately by using the S(p)-Clarkson or S(c)-Clarkson integration method; however, the S(c)-Clarkson integration method is more straightforward because the S(c) factor expresses the in-air X-ray output factor. It has been found that when the MLC field is relatively much smaller than the main collimator field, the Sc factor can be accurately evaluated by introducing the small segment correction (SSC) factor (except for the case in which the MLC field is less than 1 x 1 cm(2)). It has also been found that both the S(p) factor and the tissue-phantom ratio (TPR) can be precisely evaluated by introducing the F(MLC) factor in cases in which the ratio of the MLC equivalent square field side to the main collimator equivalent square field side is less than about 0.7.

[Method of estimating 10 MV X-ray irregular field dose using the collimator scatter factor (Sc) and phantom scatter factor (Sp)].

It has been found that in general 10 MV X-ray dose calculation can be made accurately for multi-leaf collimator irregular fields by using the total scatter factor (S(cp)), collimator scatter factor (S(c)), and phantom scatter factor (S(p)) proposed by Khan et al. With respect to the collimator scatter factor (S(c)), we used the field-mapping method of Kim et al. to obtain equivalent square fields of irregular fields (the collimator reverse effect can be accurately dissolved using the field-mapping method). Even for extremely small multi-leaf fields compared with the main collimator opening, X-ray output calculations could be made accurately by introducing the small segment correction (SSC) factor. With respect to the phantom scatter factor (S(p)), highly accurate calculations could be made for irregular field irradiation by applying an F(MLC) (MLC radiation leakage) factor to the equivalent square field (in cases in which the ratio of the multi-leaf equivalent square field side to the main collimator equivalent square field side is less than 0.6). However, it has been found that highly accurate dose calculations can, in general, be performed when the main collimator is limited just at the opening determined by the multi-leaf collimator field.

[Comments on evaluation method for equivalent square fields to the collimator scatter factors of rectangular fields].

In the measurement of 4 MV and 10 MV X-ray collimator scatter factors (S(c)), the method of using an acrylic mini-phantom showed no significant differences between cases in which the chamber axis was either parallel or perpendicular to the beam axis. Chamber readings with an aluminum or acrylic build-up cap were not reflected by contaminant electrons when the chamber axis was parallel to the beam axis. On the basis of the data on 4 MV and 10 MV X-ray collimator Sc measured using an acrylic mini-phantom, we examined three methods of obtaining square fields equivalent to rectangular fields, and reached the following conclusions: (1) The A/P method was not accurate because it did not take into account the structure of the radiation head. (2) Regarding the geometrical weight factor (k) used in the field-mapping method, more accurate k values were obtained when using the geometrical places of the flattening filter (or the second source, taken from the concept of extra-focal radiation), the upper and lower collimators, and the chamber, rather than when using the geometrical places of the source, the upper and lower collimators, and the chamber. (3) The most accurate k values could, in general, be obtained when determined on the basis of measured S(c) data.