Dosimetric impact of rectum and bladder anatomy and intrafractional prostate motion on hypofractionated prostate radiation therapy

Objective The objective of this study was to evaluate the dosimetric impact on hypofractionated prostate radiation therapy of two geometric uncertainty sources: rectum and bladder filling and intrafractional prostate motion.Materials and methodsThis prospective study included 544 images (375 pre-treatment cone-beam CT [CBCT] and 169 post-treatment CBCT) from 15 prostate adenocarcinoma patients. We recalculated the dose on each pre-treatment CBCT once the positioning errors were corrected. We also recalculated two dose distributions on each post-treatment CBCT, either using or not intrafractional motion correction. A correlation analysis was performed between CBCT-based dose and rectum and bladder filling as well as intrafraction prostate displacements.ResultsNo significant differences were found between administered and planned rectal doses. However, we observed an increase in bladder dose due to a lower bladder filling in 66% of treatment fractions. These differences were reduced at the end of the fraction since the lower bladder volume was compensated by the filling during the treatment session. A statistically significant reduction in target volume coverage was observed in 27% of treatment sessions and was correlated with intrafractional prostate motion in sagittal plane > 4 mm.ConclusionsA better control of bladder filling is recommended to minimize the number of fractions in which the bladder volume is lower than planned. Fiducial mark tracking with a displacement threshold of 5 mm in any direction is recommended to ensure that the prescribed dose criteria are met. (AU)

Dosimetric impact of rectum and bladder anatomy and intrafractional prostate motion on hypofractionated prostate radiation therapy.

OBJECTIVE: The objective of this study was to evaluate the dosimetric impact on hypofractionated prostate radiation therapy of two geometric uncertainty sources: rectum and bladder filling and intrafractional prostate motion. MATERIALS AND METHODS: This prospective study included 544 images (375 pre-treatment cone-beam CT [CBCT] and 169 post-treatment CBCT) from 15 prostate adenocarcinoma patients. We recalculated the dose on each pre-treatment CBCT once the positioning errors were corrected. We also recalculated two dose distributions on each post-treatment CBCT, either using or not intrafractional motion correction. A correlation analysis was performed between CBCT-based dose and rectum and bladder filling as well as intrafraction prostate displacements. RESULTS: No significant differences were found between administered and planned rectal doses. However, we observed an increase in bladder dose due to a lower bladder filling in 66% of treatment fractions. These differences were reduced at the end of the fraction since the lower bladder volume was compensated by the filling during the treatment session. A statistically significant reduction in target volume coverage was observed in 27% of treatment sessions and was correlated with intrafractional prostate motion in sagittal plane > 4 mm. CONCLUSIONS: A better control of bladder filling is recommended to minimize the number of fractions in which the bladder volume is lower than planned. Fiducial mark tracking with a displacement threshold of 5 mm in any direction is recommended to ensure that the prescribed dose criteria are met.

Application of discrete cosine transform to assess the effect of tumor motion variations on the definition of ITV in lung and liver SBRT.

PURPOSE: To use Discrete Cosine Transform to include tumor motion variations on ITV definition of SBRT patients. METHODS: Data from 66 patients was collected. 2D planar fluoroscopy images (FI) were available for 54 patients. Daily CBCT projections (CBCTp) from 29 patients were employed to measure interfraction amplitude variability. Systematic amplitude variations were obtained from 17 patients with data from both FI and CBCTp. Tumor motion curves obtained from FI were characterized with a Cosine model (CM), based on cosine functions to the power of 2, 4 or 6, and DCT. Performance of both models was evaluated by means of R2 coefficient and by comparing their results on Internal Target Volume (ITV) margins against those calculated from original tumor motion curves. Amplitude variations from CBCTp, as well as estimations of baseline shift variations were added to the DCT model to account for their effect on ITV margins. RESULTS: DCT replicated tumor motion curves with a mean R2 values for all patients of 0.86, 0.91 and 0.96 for the lateral (LAT), anterior-posterior (AP) and cranio-caudal (CC) directions respectively. CM yielded worst results, with R2 values of 0.64, 0.61 and 0.74 in the three directions. Interfraction amplitude variation increased ITV margins by a 9%, while baseline shift variability implied a 40% and 80-100% increase for normalized values of baseline shift of 0.2 and 0.4 respectively. CONCLUSIONS: Probability distribution functions of tumor positions can be successfully characterized with DCT. This permits to include tumor motion variablilities obtained from patient population into patient specific ITVs.

Impact of rectum and bladder anatomy in intrafractional prostate motion during hypofractionated radiation therapy.

BACKGROUND: The objective was to determine the magnitude of the prostate intrafractional motion relative to bony pelvis anatomy, and to evaluate the relationship between this displacement and some clinical and anatomical variables. MATERIALS AND METHODS: The prospective study consisted of 544 images (375 pre-treatment CBCT and 169 post-treatment CBCT) from 15 prostate adenocarcinoma patients that were used for intrafractional prostate motion determination. In addition, two radiation oncologists re-contoured the bladder and rectum on each CBCT according to the patient's anatomy of the day. ANOVA and correlation analysis followed by linear regression analysis were performed to identify clinical or anatomical variables that predict large prostate intrafractional motion. RESULTS: Prostate shift increased in patients with hormone therapy (p ≤ 0.02). The regression analysis showed that patients with large bladder intrafractional filling (p < 0.01) and a large bladder volume difference from planning CT were more likely to experience bigger longitudinal prostate motion (> 3 mm). Recommended bladder size values: anterior-posterior size ≤ 10 cm and anterior-posterior/cranio-caudal ratio ≤ 1.7, both parameters measured in the midsagittal prostate plane, were defined. CONCLUSIONS: The treatment margin should not be reduced for those patients who were treated with hormone therapy and/or whose rectum or bladder was far from complying the preparation protocol conditions.

Reduced late urinary toxicity with high-dose intensity-modulated radiotherapy using intra-prostate fiducial markers for localized prostate cancer

Background/purpose. To evaluate the impact of intensity-modulated radiotherapy (IMRT) with intra-prostate fiducial markers image-guided radiotherapy (IGRT) on the incidence of late urinary toxicity compared to 3D conformal radiotherapy (3DCRT) for patients with prostate cancer (PC). Methods and materials. We selected 733 consecutive patients with localized PC treated with dose-escalation radiotherapy between 2001 and 2014. Eligibility criteria were radiation dose >72.0 Gy, no pelvic RT and minimum follow-up 24 months. 438 patients were treated with 3DCRT and 295 with IMRT. Acute and late urinary complications were assessed using the EORTC/RTOG and CTCAEs v3.0 definition. The Cox regression model was used to compare grade ≥2 urinary toxicity between both techniques. The median follow-up was 75 months (range 24-204). Results. The median isocenter radiation dose was 78.7 Gy for 3DCRT and 80.7 Gy for IMRT/IGRT (p < 0.001). The 5-year incidence of late grade ≥2 urinary toxicity was 6.4% for IMRT and 10.8% for 3DCRT [hazard ratio (HR) 0.575, p = 0.056]. The corresponding 5-year estimates of late grade ≥2 hematuria were 2% for IMRT and 5.3% for 3DCRT (HR 0.296, p = 0.024). On multivariate analysis, the antecedent of prior transurethral resection of the prostate was also a strong predictor of a higher risk of urinary complications (HR 2.464, p = 0.002) and of hematuria (HR 5.196, p < 0.001). Conclusion. Compared with 3DCRT, high-dose IMRT/IGRT is associated with a lower rate of late urinary complications in spite of higher radiation dose (AU)

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Reduced late urinary toxicity with high-dose intensity-modulated radiotherapy using intra-prostate fiducial markers for localized prostate cancer.

BACKGROUND/PURPOSE: To evaluate the impact of intensity-modulated radiotherapy (IMRT) with intra-prostate fiducial markers image-guided radiotherapy (IGRT) on the incidence of late urinary toxicity compared to 3D conformal radiotherapy (3DCRT) for patients with prostate cancer (PC). METHODS AND MATERIALS: We selected 733 consecutive patients with localized PC treated with dose-escalation radiotherapy between 2001 and 2014. Eligibility criteria were radiation dose >72.0 Gy, no pelvic RT and minimum follow-up 24 months. 438 patients were treated with 3DCRT and 295 with IMRT. Acute and late urinary complications were assessed using the EORTC/RTOG and CTCAEs v3.0 definition. The Cox regression model was used to compare grade ≥2 urinary toxicity between both techniques. The median follow-up was 75 months (range 24-204). RESULTS: The median isocenter radiation dose was 78.7 Gy for 3DCRT and 80.7 Gy for IMRT/IGRT (p < 0.001). The 5-year incidence of late grade ≥2 urinary toxicity was 6.4% for IMRT and 10.8% for 3DCRT [hazard ratio (HR) 0.575, p = 0.056]. The corresponding 5-year estimates of late grade ≥2 hematuria were 2% for IMRT and 5.3% for 3DCRT (HR 0.296, p = 0.024). On multivariate analysis, the antecedent of prior transurethral resection of the prostate was also a strong predictor of a higher risk of urinary complications (HR 2.464, p = 0.002) and of hematuria (HR 5.196, p < 0.001). CONCLUSION: Compared with 3DCRT, high-dose IMRT/IGRT is associated with a lower rate of late urinary complications in spite of higher radiation dose.

Methodology for registration of distended rectums in pelvic CT studies.

PURPOSE: Accurate delineation of the rectum is of high importance in off-line adaptive radiation therapy since it is a major dose-limiting organ in prostate cancer radiotherapy. The intensity-based deformable image registration (DIR) methods cannot create a correct spatial transformation if there is no correspondence between the template and the target images. The variation of rectal filling, gas, or feces, creates a non correspondence in image intensities that becomes a great obstacle for intensity-based DIR. METHODS: In this study the authors have designed and implemented a semiautomatic method to create a rectum mask in pelvic computed tomography (CT) images. The method, that includes a DIR based on the demons algorithm, has been tested in 13 prostate cancer cases, each comprising of two CT scans, for a total of 26 CT scans. RESULTS: The use of the manual segmentation in the planning image and the proposed rectum mask method (RMM) method in the daily image leads to an improvement in the DIR performance in pelvic CT images, obtaining a mean value of overlap volume index = 0.89, close to the values obtained using the manual segmentations in both images. CONCLUSIONS: The application of the RMM method in the daily image and the manual segmentations in the planning image during prostate cancer treatments increases the performance of the registration in presence of rectal fillings, obtaining very good agreement with a physician's manual contours.

Three-dimensional quantitative evaluation method of nonrigid registration algorithms for adaptive radiotherapy.

PURPOSE: Current radiotherapy is progressing to the concept of adaptive radiotherapy, which implies the adaptation of planning along the treatment course. Nonrigid registration is an essential image processing tool for adaptive radiotherapy and image guided radiotherapy, and the three-dimensional (3D) nature of the current radiotherapy techniques requires a 3D quantification of the registration error that existing evaluation methods do not cover appropriately. The authors present a method for 3D evaluation of nonrigid registration algorithms' performance, based on organ delineations, capable of working with near-spherical volumes even in the presence of concavities. METHODS: The evaluation method is composed by a volume shape description stage, developed using a new ad hoc volume reconstruction algorithm proposed by the authors, and an error quantification stage. The evaluation method is applied to the organ delineations of prostate and seminal vesicles, obtained by an automatic segmentation method over images of prostate cancer patients treated with intensity modulated radiation therapy. RESULTS: The volume reconstruction algorithm proposed has been shown to accurately model complex 3D surfaces by the definition of clusters of control points. The quantification method, inspired by the Haussdorf-Chebysev distance, provides a measure of the largest registration error per control direction, defining a valid metric for concave-convex volumes. Summarizing, the proposed evaluation methodology presents accurate results with a high spatial resolution in a negligible computation time in comparison with the nonrigid registration time. CONCLUSIONS: Experimental results show that the metric selected for quantifying the registration error is of utmost importance in a quantitative evaluation based on measuring distances between volumes. The accuracy of the volume reconstruction algorithm is not so relevant as long as the reconstruction is tight enough on the actual volume of the organ. The new evaluation method provides a smooth and accurate volume reconstruction for both the reference and the registered organ, and a complete 3D description of nonrigid registration algorithms' performance, resulting in a useful tool for study and comparison of registration algorithms for adaptive radiotherapy.

Dose escalation with three-dimensional conformal radiotherapy for prostate cancer. Is more dose really better in high-risk patients treated with androgen deprivation?

AIMS: To determine the effect of radiation dose on biochemical control in prostate cancer patients treated in a single institution with three-dimensional conformal radiotherapy (3DCRT) and the additional effect of androgen deprivation in prostate cancer patients. MATERIALS AND METHODS: In total, 363 men with T1-T3b prostate cancer treated in a sequential radiation dose-escalation trial from 66.0 to 84.1 Gy (International Commission Radiation Units and Measurement [ICRU] reference point) between 1995 and 2003, and with a minimum follow-up of 24 months, were included in the analysis. One hundred and forty-eight (41%) men were treated with 3DCRT alone; 74 (20%) men received neoadjuvant androgen deprivation (NAD) 4-6 months before and during 3DCRT; and 141 (39%) men received NAD and adjuvant androgen deprivation (AAD) 2 years after 3DCRT. Univariate, stratified and multivariate analyses were carried out separately for defined risk groups (low, intermediate and high) to determine the effect of radiation dose on biochemical control and its interaction with hormonal manipulation and clinical prognostic variables. RESULTS: The median follow-up was 59 months (range 24-147 months). The actuarial biochemical disease-free survival (bDFS) at 5 years for all patients was 75% (standard error 3%). For low-risk patients, the bDFS was 82% (standard error 5%), for intermediate-risk patients it was 64% (standard error 6%) and for high-risk patients it was 77% (standard error 3%) (P = 0.031). In stratified and multivariate analyses, high-dose 3DCRT for all risk groups, and for high-risk patients, the use of long-term AAD vs NAD, contributed independently and significantly to improve the outcome of prostate cancer patients. CONCLUSION: The present study indicates an independent benefit on biochemical outcome of high-dose 3DCRT for low-, intermediate- and high-risk patients and of long-term AAD in high-risk prostate cancer patients.

[Dose escalation with three dimensional conformal radiotherapy for prostate cancer: more is better?]. / Intensificación de dosis con radioterapia conformacional 3D en cancer de próstata. Mas dosis es mejor?

PURPOSE: The present study was undertaken to determine the effect of radiation dose on biochemical control and morbidity in prostate cancer patients. MATERIALS AND METHODS: Between 1995 and 2003, 360 patients with T1-T3b prostate cancer were treated in a sequential radiation dose escalation trial from 66.0 to 82.6 Gy. These patients were prospectively assigned to 1 of 3 prognostic groups according to risk factors: a) low risk patients were treated with 3DCRT alone; b) intermediate risk patients were allocated to receive neoadjuvant AD (NAD) 4-6 months prior and during 3DCRT; and c) high-risk received NAD and adjuvant AD (AAD) 2 years after 3DCRT. RTOG/EORTC toxicity score was used to analyze late complications RESULTS: Median follow-up was 48 months (12-138). The actuarial biochemical disease free survival (bDFS) at 4 years for low risk, intermediate risk and high risk patients was 88%, 68% and 79% respectively. Stratified and multivariate analysis showed that higher radiation dose (>76 Gy) (p=0.0053) and the use of AAD for high risk patients (p=0.0046) correlated significantly with an improvement of bDFS for all patients. The incidence of late grade 2 rectal and urinary bleeding were 7% and 11% respectively. CONCLUSION: The present study confirms an independent benefit of high-dose (> 76 Gy) radiation therapy and long-term AAD in high-risk prostate cancerpatients.

Intensificación de dosis con radioterapia conformacional 3D en cáncer de próstata. ¿Más dosis es mejor? / Dose escalation with three dimensional conformal radiotherapy for prostate cancer: more is better?

Objetivo: Determinar el efecto de la dosis de radiación en los resultados de control bioquímico y morbilidad en pacientes con cáncer de próstata. Material y Métodos: Entre 1995 y 2003, 360 pacientes con cáncer de próstata T1-T3b fueron tratados conRTC3D (66,0 Gy-82,6 Gy). Los pacientes fueron asignados a uno de tres grupos pronósticos: a) bajo riesgo: tratados con RTC3D exclusiva; b) riesgo intermedio tratados con deprivación androgénica (DA) neoadyuvante 4-6meses previos y durante RTC3D; y c) alto riesgo: DA previa, durante y dos años tras RTC3D. Para el análisis de toxicidad tardía se empleó la escala de RTOG/EORTC. Resultados: Con una mediana de seguimiento de 48 meses (12-138), la supervivencia libre de fracaso bioquímico (SLFB) a 4 años en pacientes de bajo riesgo fue del 88%, en los de riesgo intermedio fue del 68% y en los de alto riesgo del 79%. En el análisis estratificado del efecto de la dosis de RTC3D controlado por el uso de hormonoterapia, y en el análisis multivariante, tanto la dosis alta de irradiación (>76 Gy) (p=0,0053), como el empleo de DA durante dos años en alto riesgo (p=0,0046) se correlacionan de forma independiente con un mejor control bioquímico. La incidencia de sangrado rectal y urinario grado 2 fue del 7% y 11% respectivamente. Conclusión: Estos datos confirman que tanto la RTC3D a dosis altas como la asociación de DA en pacientes de alto riesgo contribuyen de forma independiente a mejorar de forma significativa los resultados del tratamiento de los pacientes con cáncer de próstata (AU)

Purpose: The present study was undertaken to determine the effect of radiation dose on biochemical control and morbidity in prostate cancer patients. Materials and Methods: Between 1995 and 2003, 360 patients with T1-T3b prostate cancer were treated in a sequential radiation dose escalation trial from 66.0 to 82.6 Gy. These patients were prospectively assigned to 1 of 3 prognostic groups according to risk factors: a) low risk patients were treated with 3DCRT alone; b) intermediate risk patients were allocated to receive neoadjuvant AD (NAD) 4-6 months prior and during 3DCRT; and c) highrisk received NAD and adjuvant AD (AAD) 2 years after 3DCRT. RTOG/EORTC toxicity score was used to analyze late complications. Results: Median follow-up was 48 months (12-138). The actuarial biochemical disease free survival (bDFS) at 4 years for low risk, intermediate risk and high risk patients was 88%, 68% and 79% respectively. Stratified and multivariate analysis showed that higher radiation dose (>76 Gy) (p=0.0053) and the use of AAD for high risk patients (p=0.0046) correlated significantly with an improvement of bDFS for all patients. The incidence of late grade 2 rectal and urinary bleeding were 7% and 11% respectively. Conclusion: The present study confirms an independent benefit of high-dose (> 76 Gy) radiation therapy and long-term AAD in high-risk prostate cancer patients (AU)

Phylogenetic relationships in Nicotiana (Solanaceae) inferred from multiple plastid DNA regions.

For Nicotiana, with 75 naturally occurring species (40 diploids and 35 allopolyploids), we produced 4656bp of plastid DNA sequence for 87 accessions and various outgroups. The loci sequenced were trnL intron and trnL-F spacer, trnS-G spacer and two genes, ndhF and matK. Parsimony and Bayesian analyses yielded identical relationships for the diploids, and these are consistent with other data, producing the best-supported phylogenetic assessment currently available for the genus. For the allopolyploids, the line of maternal inheritance is traced via the plastid tree. Nicotiana and the Australian endemic tribe Anthocercideae form a sister pair. Symonanthus is sister to the rest of Anthocercideae. Nicotiana sect. Tomentosae is sister to the rest of the genus. The maternal parent of the allopolyploid species of N. sect. Polydicliae were ancestors of the same species, but the allopolyploids were produced at different times, thus making such sections paraphyletic to their extant diploid relatives. Nicotiana is likely to have evolved in southern South America east of the Andes and later dispersed to Africa, Australia, and southwestern North America.

Modulación de intensidad. Principios básicos. Implementación / Intensy Modulation. Basic principles. Implementation

La radioterapia por modulación de intensidad IMRT se ha presentado como una de la opciones mas prometedoras en el tratamiento radioterápico por su capacidad para el diseño y aplicación de tratamientos de alta conformación en localizaciones donde la topología del Volumen blanco- Órganos de riesgo es desfavorable. Esta lección es un resumen general de los distintos pasos y elementos necesarios para la realización de IMRT en comparación con la radioterapia conformacional tridimensional estándar, haciendo especial hincapié en la generación de haces modulados mediante multiláminas dinámico (dMLC). Por motivos de brevedad únicamente se trataran de forma somera los aspectos del control de calidad dosimétrico asociado (AU)

Exact analytical solution of the convolution integral equation for a general profile fitting function and Gaussian detector kernel.

One of the most important aspects in the metrology of radiation fields is the problem of the measurement of dose profiles in regions where the dose gradient is large. In such zones, the 'detector size effect' may produce experimental measurements that do not correspond to reality. Mathematically it can be proved, under some general assumptions of spatial linearity, that the disturbance induced in the measurement by the effect of the finite size of the detector is equal to the convolution of the real profile with a representative kernel of the detector. In this work the exact relation between the measured profile and the real profile is shown, through the analytical resolution of the integral equation for a general type of profile fitting function using Gaussian convolution kernels.

Experimental determination of the convolution kernel for the study of the spatial response of a detector.

One of the most important parameters in the characterization of a detector is its spatial convolution kernel. This kernel contains all of the information about the influence that the detector size has on the measured beam profile. In this paper we present an experimental method for the determination of the spatial convolution kernel for commonly used detectors that are employed in the x-ray profile measurement: film + densitometer, diode, and ionization minichamber. Our work is based on first assuming a step function pattern on a photographic film is known and is a perfect step function. The kernel of the densitometer system was then derived from the deconvolution of the scanned profile to the step function. Next a film was exposed to a penumbra area of an x-ray beam from a linac. The film was scanned using the same densitometer. The "real profile" that emerges from a linear accelerator was derived by the deconvolution of the scanned profile using the now known kernel of the film densitometer. Under the same irradiation condition the x-ray profile was measured with other detectors and with this information we obtained the convolution kernels for these detectors by solving numerically their basic convolution integrals. The results show that the Gaussian convolution kernel is the most consistent with the measurements. The best numerical values for the FWHM of the kernels are 1.1 mm, 2.2 mm, and 5.4 mm for densitometer, diode, and minichamber, respectively.