Influence of Ku86 and XRCC4 expression in uterine cervical cancer on the response to preoperative radiotherapy.

DNA double-strand breaks (DSB) are severe damages induced by ionizing radiation. Non-homologous end joining (NHEJ) is a major mechanism for repairing DSB. Immunohistochemical analysis of proteins involved in NHEJ, such as Ku86 and XRCC4 (X-ray repair cross-complementing protein 4) may be useful for predicting tumor radiosensitivity. We examined the relationship between expression of DSB-related proteins in biopsy specimens of uterine cervical cancer and the pathological effect of 40 Gy of preoperative radiotherapy. 119 patients with uterine cervical cancer were treated between 2000 and 2011. Pathological effects of preoperative radiotherapy were classified by examining hysterectomy specimens. Patients with complete response (pCR) had a significantly better overall 5-year survival rate than those without pCR (96.3 vs. 76.9 %, P = 0.02). The pCR rate was significantly higher in patients with low Ku86 and XRCC4 expression than in other patients (47.4 vs. 21.3 %, P = 0.04). Logistic regression analysis also demonstrated that low Ku86 and XRCC4 expression was a significant predictor of pCR (P = 0.03). Patients with high Ku86 and XRCC4 expression had a significantly lower 5-year metastasis-free rate than others (79.3 vs. 93.5 %, P = 0.02). Proteins involved with NHEJ might have an influence on results of radiotherapy for uterine cervical cancer.

Dosimetric Comparison Study of Proton Therapy Using Line Scanning versus Passive Scattering and Volumetric Modulated Arc Therapy for Localized Prostate Cancer.

BACKGROUND: The proton irradiation modality has transitioned from passive scattering (PS) to pencil beam scanning. Nevertheless, the documented outcomes predominantly rely on PS. METHODS: Thirty patients diagnosed with prostate cancer were selected to assess treatment planning across line scanning (LS), PS, and volumetric modulated arc therapy (VMAT). Dose constraints encompassed clinical target volume (CTV) D98 ≥ 73.0 Gy (RBE), rectal wall V65 < 17% and V40 < 35%, and bladder wall V65 < 25% and V40 < 50%. The CTV, rectal wall, and bladder wall dose volumes were calculated and evaluated using the Freidman test. RESULTS: The LS technique adhered to all dose limitations. For the rectal and bladder walls, 10 (33.3%) and 21 (70.0%) patients in the PS method and 5 (16.7%) and 1 (3.3%) patients in VMAT, respectively, failed to meet the stipulated requirements. The wide ranges of the rectal and bladder wall volumes (V10-70) were lower with LS than with PS and VMAT. LS outperformed VMAT across all dose-volume rectal and bladder wall indices. CONCLUSION: The LS method demonstrated a reduction in rectal and bladder doses relative to PS and VMAT, thereby suggesting the potential for mitigating toxicities.

Analysis of the optimum internal margin for respiratory-gated radiotherapy using end-expiratory phase assessments using a motion phantom.

We aimed to optimize internal margin (IM) determination for respiratory-gated radiotherapy using end-expiratory phase assessments using a motion phantom. Four-dimensional computed tomography (4D CT) data were acquired using a GE LightSpeed RT CT scanner, a respiratory-gating system, and a motion phantom designed to move sinusoidally. To analyze the accuracy of 4D CT temporal resolution, a 25.4 mm diameter sphere was inserted into the motion phantom, and we measured the differences in sphere diameters between static and end-exhalation phase images. In addition, the IM obtained from the maximum intensity projection within the gating window (MIP(GW)) image was compared to theoretical value. Cranial-caudal motion displacement ranged from 5.0 to 30.0 mm, and the respiratory period ranged from 2.0 to 6.0 sec. Differences in sphere diameters between static and end-exhalation phase images ranged from 0.37 to 4.6 mm, with 5.0-mm and 30 mm target displacements, respectively. Differences between the IM obtained from the MIP(GW) and the theoretical values ranged from 1.12 to 6.23 mm with 5.0mm and 30 mm target displacements, respectively. These differences increased in proportion to the target velocity due to a motion artifact generated during tube rotation. In this study, the IMs obtained using the MIPGW image were overestimated in all cases. We therefore propose that the internal target volume (ITV) for respiratory-gated radiotherapy should be determined by adding the calculated value to the end-exhalation phase image. We also demonstrate a methodology for subtracting motion artifacts from the ITV using a motion phantom.

A dosimetry study of the Oncoseed 6711 using glass rod dosimeters and EGS5 Monte Carlo code in a geometry lacking radiation equilibrium scatter conditions.

PURPOSE: The aim of this study was to develop a dose calculation method which is applicable to the interseed attenuation and the geometry lacking the equilibrium radiation scatter conditions in brachytherapy. METHODS: The dose obtained from measurement with a radiophotoluminescent glass rod dosimeter (GRD) was compared to the dose calculated with the Monte Carlo (MC) code "EGS5," using the 125I source structure detailed in by Kennedy et al. The GRDs were irradiated with 125I Oncoseed 6711 in a human head phantom. The phantom was a cylinder made of 2 mm thick PMMA with a diameter of 18 cm and length of 16 cm. Some of the GRD positions were so close to the phantom surface that the backscatter margin was less than 5 cm, insufficient for photons. RESULTS: The EGS5 simulations were found to reproduce the relative dose distributions as measured with the GRDs to within 25% uncertainty in the geometry lacking the equilibrium radiation scatter conditions. The absolute value of the GRD measurement agreed with the American Association of Physicist in Medicine Task Group No 43 Updated Protocol (AAPM-TG43U1) formalism to within 3% of the reference point (r = 1 cm, theta = 90 degrees), where the TG43U1 is especially reliable because of the abundant data accumulation in composing the formalism. The factor to normalize the measured or calculated dose to the TG43U1 estimate at the reference point was evaluated to be 0.97 for the GRD measurement and 1.8 for the MC calculation, which uses the integration of the apparent activity with the time as the amount of disintegration during the irradiation. Also, F(r,theta) and g(r) estimated by this calculation method were consistent with those proposed in the TG43U1. CONCLUSIONS: The results of this investigation support the validity of both the MC calculation method and GRD measurement in this study as well as the TG-43U1 formalism. Also, this calculation is applicable to interseed attenuation and the geometry lacking the equilibrium radiation scatter.

An in vitro verification of strength estimation for moving an 125I source during implantation in brachytherapy.

This study aims to demonstrate the feasibility of a method for estimating the strength of a moving brachytherapy source during implantation in a patient. Experiments were performed under the same conditions as in the actual treatment, except for one point that the source was not implanted into a patient. The brachytherapy source selected for this study was 125I with an air kerma strength of 0.332 U (µGym2h-1), and the detector used was a plastic scintillator with dimensions of 10 cm × 5 cm × 5 cm. A calibration factor to convert the counting rate of the detector to the source strength was measured and then the accuracy of the proposed method was investigated for a manually driven source. The accuracy was found to be under 10% when the shielding effect of additional needles for implantation at other positions was corrected, and about 30% when the shielding was not corrected. Even without shielding correction, the proposed method can detect dead/dropped source, implantation of a source with the wrong strength, and a mistake in the number of the sources implanted. Furthermore, when the correction was applied, the achieved accuracy came close to within 7% required to find the Oncoseed 6711 (125I seed with unintended strength among the commercially supplied values of 0.392, 0.462 and 0.533 U).

Interinstitutional variations in planning for stereotactic body radiation therapy for lung cancer.

PURPOSE: The aim of this study was to assess interinstitutional variations in planning for stereotactic body radiation therapy (SBRT) for lung cancer before the start of the Japan Clinical Oncology Group (JCOG) 0403 trial. METHODS AND MATERIALS: Eleven institutions created virtual plans for four cases of solitary lung cancer. The created plans should satisfy the target definitions and the dose constraints for the JCOG 0403 protocol. RESULTS: FOCUS/XiO (CMS) was used in six institutions, Eclipse (Varian) in 3, Cadplan (Varian) in one, and Pinnacle3 (Philips/ADAC) in one. Dose calculation algorithms of Clarkson with effective path length correction and superposition were used in FOCUS/XiO; pencil beam convolution with Batho power law correction was used in Eclipse and Cadplan; and collapsed cone convolution superposition was used in Pinnacle3. For the target volumes, the overall coefficient of variation was 16.6%, and the interinstitutional variations were not significant. For maximal dose, minimal dose, D95, and the homogeneity index of the planning target volume, the interinstitutional variations were significant. The dose calculation algorithm was a significant factor in these variations. No violation of the dose constraints for the protocol was observed. CONCLUSION: There can be notable interinstitutional variations in planning for SBRT, including both interobserver variations in the estimate of target volumes as well as dose calculation effects related to the use of different dose calculation algorithms.

Dosimetric verification in participating institutions in a stereotactic body radiotherapy trial for stage I non-small cell lung cancer: Japan clinical oncology group trial (JCOG0403).

A multicentre phase II trial of stereotactic body radiotherapy for T1N0M0 non-small cell lung cancer was initiated in Japan as the Japan Clinical Oncology Group trial (JCOG0403). Before starting the trial, a decision was made to evaluate the treatment machine and treatment planning in participating institutions to minimize the variations of the prescription dose between the institutions. We visited the 16 participating institutions and examined the absolute dose at the centre of a simulated spherical tumour of 3.0 cm diameter in the lung using the radiation treatment planning systems in each institution. A lung phantom for stereotactic body radiotherapy (SBRT) was developed and used for the treatment planning and film dosimetry. In the JCOG radiotherapy study group, the no model-based calculation algorithm or the model-based calculation algorithm with a dose kernel unscaled for heterogeneities were selected for use in the initial SBRT trials started in 2004, and the model-based calculation algorithm with a dose kernel scaled for heterogeneities was selected for the coming trial. The findings of this study suggest that the clinical results of lung SBRT trials should be carefully evaluated in comparison with the actual dose given to patients.

Results and DVH analysis of late rectal bleeding in patients treated with 3D-CRT or IMRT for localized prostate cancer.

In patients undergoing radiotherapy for localized prostate cancer, dose-volume histograms and clinical variables were examined to search for correlations between radiation treatment planning parameters and late rectal bleeding. We analyzed 129 patients with localized prostate cancer who were managed from 2002 to 2010 at our institution. They were treated with 3D conformal radiation therapy (3D-CRT, 70 Gy/35 fractions, 55 patients) or intensity-modulated radiation therapy (IMRT, 76 Gy/38 fractions, 74 patients). All radiation treatment plans were retrospectively reconstructed, dose-volume histograms of the rectum were generated, and the doses delivered to the rectum were calculated. Time to rectal bleeding ranged from 9-53 months, with a median of 18.7 months. Of the 129 patients, 33 patients had Grade 1 bleeding and were treated with steroid suppositories, while 25 patients with Grade 2 bleeding received argon plasma laser coagulation therapy (APC). Three patients with Grade 3 bleeding required both APC and blood transfusion. The 5-year incidence rate of Grade 2 or 3 rectal bleeding was 21.8% for the 3D-CRT group and 21.6% for the IMRT group. Univariate analysis showed significant differences in the average values from V65 to V10 between Grades 0-1 and Grades 2-3. Multivariate analysis demonstrated that patients with V65 ≥ 17% had a significantly increased risk (P = 0.032) of Grade 2 or 3 rectal bleeding. Of the 28 patients of Grade 2 or 3 rectal bleeding, 17 patients (60.7%) were cured by a single session of APC, while the other 11 patients required two sessions. Thus, none of the patients had any further rectal bleeding after the second APC session.

Relation between Ku80 and microRNA-99a expression and late rectal bleeding after radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: Late rectal bleeding is one of the severe adverse events after radiotherapy for prostate cancer. New biomarkers are needed to allow a personalized treatment. MATERIALS AND METHODS: Four patients each with grade 0-1 or grade 2-3 rectal bleeding were randomly selected for miRNA array to examine miRNA expression in peripheral blood lymphocytes (PBLs). Based on results of miRNA array, 1 of 348 miRNAs was selected for microRNA assays. Then, expression of DNA-dependent protein kinase mRNA and miR-99a was analyzed in the PBLs of 97 patients. PBLs were exposed to 4Gy of X-ray ex-vivo. RESULTS: In the discovery cohort, grade 2-3 rectal bleeding was significantly higher in the Ku80 <1.09 expression group compared with ⩾1.09 group (P=0.011). In radiation-induced expression of miR-99a, grade 2-3 rectal bleeding was significantly higher in the miR-99a IR(+)/IR(-) >0.93 group compared with ⩽0.93 group (P=0.013). Most patients with grade 2-3 rectal bleeding were in the group with low Ku80 and high miR-99a expression. In the validation cohort, similar results were obtained. CONCLUSION: A combination of low Ku80 expression and highly-induced miR-99a expression could be a promising marker for predicting rectal bleeding after radiotherapy.

A comparison of the dose distributions between the brachytherapy 125I source models, STM1251 and Oncoseed 6711, in a geometry lacking radiation equilibrium scatter conditions.

The purpose of this study was to estimate the uncertainty in the dose distribution for the (125)I source STM1251, as measured with a radiophotoluminescent glass rod dosimeter and calculated using the Monte Carlo code EGS5 in geometry that included the source structure reported by Kirov et al. This was performed at a range of positions in and on a water phantom 18 cm in diameter and 16 cm in length. Some dosimetry positions were so close to the surface that the backscatter margin was insufficient for photons. Consequently, the combined standard uncertainty (CSU) at the coverage factor k of 1 was 11.0-11.2% for the measurement and 1.8-3.6% for the calculation. The calculation successfully reproduced the measured dose distribution within 13%, with CSU at k ≤ 1.6 (P > 0.3). Dose distributions were then compared with those for the (125)I source Oncoseed 6711. Our results supported the American Association of Physicists in Medicine Task Group No. 43 Updated Protocol (TG43U1) formalism, in which STM1251 dose distributions were more penetrating than those of Oncoseed 6711. This trend was also observed in the region near the phantom surface lacking the equilibrium radiation scatter conditions. In this region, the difference between the TG43U1 formalism and the measurement and calculation performed in the present study was not significant (P > 0.3) for either of the source models. Selection of the source model based on the treatment plans according to the TG43U1 formalism will be practical.

Analysis of Prostate Deformation during a Course of Radiation Therapy for Prostate Cancer.

PURPOSE: Accurate analysis of the correlation between deformation of the prostate and displacement of its center of gravity (CoG) is important for efficient radiation therapy for prostate cancer. In this study, we addressed this problem by introducing a new analysis approach. METHOD: A planning computed tomography (CT) scan and 7 repeat cone-beam CT scans during the course of treatment were obtained for 19 prostate cancer patients who underwent three-dimensional conformal radiation therapy. A single observer contoured the prostate gland only. To evaluate the local deformation of the prostate, it was divided into 12 manually defined segments. Prostate deformation was calculated using in-house developed software. The correlation between the displacement of the CoG and the local deformation of the prostate was evaluated using multiple regression analysis. RESULTS: The mean value and standard deviation (SD) of the prostate deformation were 0.6 mm and 1.7 mm, respectively. For the majority of the patients, the local SD of the deformation was slightly lager in the superior and inferior segments. Multiple regression analysis revealed that the anterior-posterior displacement of the CoG of the prostate had a highly significant correlation with the deformations in the middle-anterior (p < 0.01) and middle-posterior (p < 0.01) segments of the prostate surface (R2 = 0.84). However, there was no significant correlation between the displacement of the CoG and the deformation of the prostate surface in other segments. CONCLUSION: Anterior-posterior displacement of the CoG of the prostate is highly correlated with deformation in its middle-anterior and posterior segments. In the radiation therapy for prostate cancer, it is necessary to optimize the internal margin for every position of the prostate measured using image-guided radiation therapy.

[Output factor calculations for intensity modulation radiation therapy as dosimetry quality assurance].

Because intensity-modulated radiation therapy (IMRT) is complicated by many small, irregular, and off-center fields, dosimetry quality assurance (QA) is extremely important. QA is performed with verifications of both dose distributions and some arbitrary point doses. In most institutes, verifications are carried out in comparison with dose values generated from radiation treatment planning systems (RTPs) and actually measured doses. However, the estimation of arbitrary point doses without RTPs should be feasible in order to perform IMRT delivery more safely and accurately in terms of the clinical aspect. In this paper, we propose a new algorithm for calculating output factors at the center point of the collimations in an IMRT field with step and shoot delivery machines in which the lower jaws were replaced with multileaf collimators (MLC). We assumed that output is independently affected by collimator scatter and total scatter according to the position of the upper jaws and each of the MLC leaves (lower jaws). Then, the two scatter factors are accurately measured when changing their position. Thus, the output factor for an irregular field could be calculated with the new algorithm. We adopted this technique for some irregular fields and actual IMRT fields for head-and-neck cancer and found that the differences between calculated and measured output values were both small and acceptable. This study suggests that our methods and this algorithm are useful for dosimetry quality assurance.

Measurement of the strength of iodine-125 seed moving at unknown speed during implantation in brachytherapy.

The aim of this study is to demonstrate the feasibility of estimating the strength of the moving radiation source during patient implantation. The requirement for the counting time was investigated by comparing the results of the measurements for the static source with those for the source moving at 2, 5, 10 and 20 cm s(-1). The utilized source was (125)I with an air-kerma strength of 0.432 U (µGym(2)h(-1)). The detector utilized was a plastic scintillation detector (8 cm × 5 cm × 2 cm in thickness) set at 8 cm away from the needle to guide the source. Experiments were conducted in order to determine the most desirable counting time. Analysis using the maximum of the measured values while the source passed through the needle indicated that the results for the moving source increased more than those for the static source as the counting time decreased. The combined standard uncertainty, with the coverage factor of 1, was within 4% at the counting time of 100 ms. This investigation supported the feasibility of the method proposed for estimating the source strength during the implantation procedure, regardless of the source speed. The method proposed is a potential option for reducing the risk of accidental replacements of sources with those of incorrect strengths.

A dosimetry method for low dose rate brachytherapy by EGS5 combined with regression to reflect source strength shortage.

The post-implantation dosimetry for brachytherapy using Monte Carlo calculation by EGS5 code combined with the source strength regression was investigated with respect to its validity. In this method, the source strength for the EGS5 calculation was adjusted with the regression, so that the calculation would reproduce the dose monitored with the glass rod dosimeters (GRDs) on a water phantom. The experiments were performed, simulating the case where one of two (125)I sources of Oncoseed 6711 was lacking strength by 4-48%. As a result, the calculation without regression was in agreement with the GRD measurement within 26-62%. In this case, the shortage in strength of a source was neglected. By the regression, in order to reflect the strength shortage, the agreement was improved up to 17-24%. This agreement was also comparable with accuracy of the dose calculation for single source geometry reported previously. These results suggest the validity of the dosimetry method proposed in this study.

Strength estimation of a moving 125Iodine source during implantation in brachytherapy: application to linked sources.

This study sought to demonstrate the feasibility of estimating the source strength during implantation in brachytherapy. The requirement for measuring the strengths of the linked sources was investigated. The utilized sources were (125)I with air kerma strengths of 8.38-8.63 U (µGy m(2) h(-1)). Measurements were performed with a plastic scintillator (80 mm × 50 mm × 20 mm in thickness). For a source-to-source distance of 10.5 mm and at source speeds of up to 200 mm s(-1), a counting time of 10 ms and a detector-to-needle distance of 5 mm were found to be the appropriate measurement conditions. The combined standard uncertainty (CSU) with the coverage factor of 1 (k = 1) was ∼15% when using a grid to decrease the interference by the neighboring sources. Without the grid, the CSU (k = 1) was ∼5%, and an 8% overestimation due to the neighboring sources was found to potentially cause additional uncertainty. In order to improve the accuracy in estimating source strength, it is recommended that the measurment conditions should be optimized by considering the tradeoff between the overestimation due to the neighboring sources and the intensity of the measured value, which influences the random error.

Uncertainty in patient set-up margin analysis in radiation therapy.

We investigated the uncertainty in patient set-up margin analysis with a small dataset consisting of a limited number of clinical cases over a short time period, and propose a method for determining the optimum set-up margin. Patient set-up errors from 555 registration images of 15 patients with prostate cancer were tested for normality using a quantile-quantile (Q-Q) plot and a Kolmogorov-Smirnov test with the hypothesis that the data were not normally distributed. The ranges of set-up errors include the set-up errors within the 95% interval of the entire patient data histogram, and their equivalent normal distributions were compared. The patient set-up error was not normally distributed. When the patient set-up error distribution was assumed to have a normal distribution, an underestimate of the actual set-up error occurred in some patients but an overestimate occurred in others. When using a limited dataset for patient set-up errors, which consists of only a small number of the cases over a short period of time in a clinical practice, the 2.5% and 97.5% intervals of the actual patient data histogram from the percentile method should be used for estimating the set-up margin. Since set-up error data is usually not normally distributed, these intervals should provide a more accurate estimate of set-up margin. In this way, the uncertainty in patient set-up margin analysis in radiation therapy can be reduced.

Analysis of post-exposure density growth in radiochromic film with respect to the radiation dose.

The post-exposure density growth (PEDG) is one of the characteristics of radiochromic film (RCF). In film dosimetry using RCF and a flatbed scanner, pixel values read out from the RCF are converted to dose (hereafter, film dose) by using a calibration curve. The aim of this study is to analyze the relationship between the pixel value read out from the RCF and the PEDG, and that between the film dose converted from the RCF and the PEDG. The film (GAFCHROMIC EBT) was irradiated with 10-MV X-rays in an ascending 11-dose-step arrangement. The pixel values of the irradiated EBT film were measured at arbitrary hours using an Epson flatbed scanner. In this study, the reference time was 24 h after irradiation, and all dose conversions from the pixel values read out from the EBT film were made using a calibration curve for 24 h after irradiation. For delivered doses of 33 and 348 cGy, the measured pixel values at 0.1 and 16 h after irradiation represented ranges of -9.6% to -0.7% and -3.9% to -0.3%, respectively, of the reference value. The relative changes between the pixel values read out from the EBT film at each elapsed time and that at the reference time decreased with increasing delivered dose. However, the difference range for all the film doses had a width of approximately -10% of the reference value at elapsed times from 0.1 to 16 h, and it showed no dependence on the delivered dose.

Dose verifications by use of liquid ionization chamber of an electronic portal imaging device (EPID).

In this study, we examined the ability of an L-EPID to verify rectangular and irregular fields and to measure the transmitted exit doses. With respect to the beam profile of rectangular and irregular fields and the doses transmitted through an inhomogeneous phantom, the L-EPID dose obtained from the L-EPID measurement was compared with the conventional dose measured by use of a 0.12-cc ionization chamber and a 3D water phantom. In the comparison of the rectangular and irregular fields, the difference in the off-center ratio (OCR) between the L-EPID dose and the conventional dose was approximately 3% in the steep-dose-gradient region (penumbra regions, >30%/cm) and approximately +/-0.5% in the gentle-dose-gradient region (5%/cm). On the other hand, the dose differences between the L-EPID and the measured doses were less than approximately 2% in the gentle-dose-gradient region. In addition, in the steep-dose-gradient region, the maximum difference was 30%. However, the differences in the distance-to-agreement (DTA) were less than approximately +/-1 mm and were unrelated to the dose gradient. These results suggest that dose verification by L-EPID is very useful in clinical applications.