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1.  Dosimetric consequences of translational and rotational errors in frame-less image-guided radiosurgery 
To investigate geometric and dosimetric accuracy of frame-less image-guided radiosurgery (IG-RS) for brain metastases.
Methods and materials
Single fraction IG-RS was practiced in 72 patients with 98 brain metastases. Patient positioning and immobilization used either double- (n = 71) or single-layer (n = 27) thermoplastic masks. Pre-treatment set-up errors (n = 98) were evaluated with cone-beam CT (CBCT) based image-guidance (IG) and were corrected in six degrees of freedom without an action level. CBCT imaging after treatment measured intra-fractional errors (n = 64). Pre- and post-treatment errors were simulated in the treatment planning system and target coverage and dose conformity were evaluated. Three scenarios of 0 mm, 1 mm and 2 mm GTV-to-PTV (gross tumor volume, planning target volume) safety margins (SM) were simulated.
Errors prior to IG were 3.9 mm ± 1.7 mm (3D vector) and the maximum rotational error was 1.7° ± 0.8° on average. The post-treatment 3D error was 0.9 mm ± 0.6 mm. No differences between double- and single-layer masks were observed. Intra-fractional errors were significantly correlated with the total treatment time with 0.7mm±0.5mm and 1.2mm±0.7mm for treatment times ≤23 minutes and >23 minutes (p<0.01), respectively. Simulation of RS without image-guidance reduced target coverage and conformity to 75% ± 19% and 60% ± 25% of planned values. Each 3D set-up error of 1 mm decreased target coverage and dose conformity by 6% and 10% on average, respectively, with a large inter-patient variability. Pre-treatment correction of translations only but not rotations did not affect target coverage and conformity. Post-treatment errors reduced target coverage by >5% in 14% of the patients. A 1 mm safety margin fully compensated intra-fractional patient motion.
IG-RS with online correction of translational errors achieves high geometric and dosimetric accuracy. Intra-fractional errors decrease target coverage and conformity unless compensated with appropriate safety margins.
PMCID: PMC3441228  PMID: 22531060
Radiosurgery; Frame-less; Frame-based; Stereotactic; Image-guidance
2.  Evolution of surface-based deformable image registration for adaptive radiotherapy of non-small cell lung cancer (NSCLC) 
To evaluate the performance of surface-based deformable image registration (DR) for adaptive radiotherapy of non-small cell lung cancer (NSCLC).
Based on 13 patients with locally advanced NSCLC, CT images acquired at treatment planning, midway and the end of the radio- (n = 1) or radiochemotherapy (n = 12) course were used for evaluation of DR. All CT images were manually [gross tumor volume (GTV)] and automatically [organs-at-risk (OAR) lung, spinal cord, vertebral spine, trachea, aorta, outline] segmented. Contours were transformed into 3D meshes using the Pinnacle treatment planning system and corresponding mesh points defined control points for DR with interpolation within the structures. Using these deformation maps, follow-up CT images were transformed into the planning images and compared with the original planning CT images.
A progressive tumor shrinkage was observed with median GTV volumes of 170 cm3 (range 42 cm3 - 353 cm3), 124 cm3 (19 cm3 - 325 cm3) and 100 cm3 (10 cm3 - 270 cm3) at treatment planning, mid-way and at the end of treatment. Without DR, correlation coefficients (CC) were 0.76 ± 0.11 and 0.74 ± 0.10 for comparison of the planning CT and the CT images acquired mid-way and at the end of treatment, respectively; DR significantly improved the CC to 0.88 ± 0.03 and 0.86 ± 0.05 (p = 0.001), respectively. With manual landmark registration as reference, DR reduced uncertainties on the GTV surface from 11.8 mm ± 5.1 mm to 2.9 mm ± 1.2 mm. Regarding the carina and intrapulmonary vessel bifurcations, DR reduced uncertainties by about 40% with residual errors of 4 mm to 6 mm on average. Severe deformation artefacts were observed in patients with resolving atelectasis and pleural effusion, in one patient, where the tumor was located around large bronchi and separate segmentation of the GTV and OARs was not possible, and in one patient, where no clear shrinkage but more a decay of the tumor was observed.
The surface-based DR performed accurately for the majority of the patients with locally advanced NSCLC. However, morphological response patterns were identified, where results of the surface-based DR are uncertain.
PMCID: PMC2804595  PMID: 20025753
3.  Investigation of the usability of conebeam CT data sets for dose calculation 
To investigate the feasibility and accuracy of dose calculation in cone beam CT (CBCT) data sets.
Kilovoltage CBCT images were acquired with the Elekta XVI system, CT studies generated with a conventional multi-slice CT scanner (Siemens Somatom Sensation Open) served as reference images. Material specific volumes of interest (VOI) were defined for commercial CT Phantoms (CATPhan® and Gammex RMI®) and CT values were evaluated in CT and CBCT images. For CBCT imaging, the influence of image acquisition parameters such as tube voltage, with or without filter (F1 or F0) and collimation on the CT values was investigated. CBCT images of 33 patients (pelvis n = 11, thorax n = 11, head n = 11) were compared with corresponding planning CT studies. Dose distributions for three different treatment plans were calculated in CT and CBCT images and differences were evaluated. Four different correction strategies to match CT values (HU) and density (D) in CBCT images were analysed: standard CT HU-D table without adjustment for CBCT; phantom based HU-D tables; patient group based HU-D tables (pelvis, thorax, head); and patient specific HU-D tables.
CT values in the CBCT images of the CATPhan® were highly variable depending on the image acquisition parameters: a mean difference of 564 HU ± 377 HU was calculated between CT values determined from the planning CT and CBCT images. Hence, two protocols were selected for CBCT imaging in the further part of the study and HU-D tables were always specific for these protocols (pelvis and thorax with M20F1 filter, 120 kV; head S10F0 no filter, 100 kV). For dose calculation in real patient CBCT images, the largest differences between CT and CBCT were observed for the standard CT HU-D table: differences were 8.0% ± 5.7%, 10.9% ± 6.8% and 14.5% ± 10.4% respectively for pelvis, thorax and head patients using clinical treatment plans. The use of patient and group based HU-D tables resulted in small dose differences between planning CT and CBCT: 0.9% ± 0.9%, 1.8% ± 1.6%, 1.5% ± 2.5% for pelvis, thorax and head patients, respectively. The application of the phantom based HU-D table was acceptable for the head patients but larger deviations were determined for the pelvis and thorax patient populations.
The generation of three HU-D tables specific for the anatomical regions pelvis, thorax and head and specific for the corresponding CBCT image acquisition parameters resulted in accurate dose calculation in CBCT images. Once these HU-D tables are created, direct dose calculation on CBCT datasets is possible without the need of a reference CT images for pixel value calibration.
PMCID: PMC2648965  PMID: 19087250
4.  Influence of increased target dose inhomogeneity on margins for breathing motion compensation in conformal stereotactic body radiotherapy 
Breathing motion should be considered for stereotactic body radiotherapy (SBRT) of lung tumors. Four-dimensional computer tomography (4D-CT) offers detailed information of tumor motion. The aim of this work is to evaluate the influence of inhomogeneous dose distributions in the presence of breathing induced target motion and to calculate margins for motion compensation.
Based on 4D-CT examinations, the probability density function of pulmonary tumors was generated for ten patients. The time-accumulated dose to the tumor was calculated using one-dimensional (1D) convolution simulations of a 'static' dose distribution and target probability density function (PDF). In analogy to stereotactic body radiotherapy (SBRT), different degrees of dose inhomogeneity were allowed in the target volume: minimum doses of 100% were prescribed to the edge of the target and maximum doses varied between 102% (P102) and 150% (P150). The dose loss due to breathing motion was quantified and margins were added until this loss was completely compensated.
With the time-weighted mean tumor position as the isocentre, a close correlation with a quadratic relationship between the standard deviation of the PDF and the margin size was observed. Increased dose inhomogeneity in the target volume required smaller margins for motion compensation: margins of 2.5 mm, 2.4 mm and 1.3 mm were sufficient for compensation of 11.5 mm motion range and standard deviation of 3.9 mm in P105, P125 and P150, respectively. This effect of smaller margins for increased dose inhomogeneity was observed for all patients. Optimal sparing of the organ-at-risk surrounding the target was achieved for dose prescriptions P105 to P118. The internal target volume concept over-compensated breathing motion with higher than planned doses to the target and increased doses to the surrounding normal tissue.
Treatment planning with inhomogeneous dose distributions in the target volume required smaller margins for compensation of breathing induced target motion with the consequence of lower doses to the surrounding organs-at-risk.
PMCID: PMC2637830  PMID: 19055768
5.  Does Intensity Modulated Radiation Therapy (IMRT) prevent additional toxicity of treating the pelvic lymph nodes compared to treatment of the prostate only? 
To evaluate the risk of rectal, bladder and small bowel toxicity in intensity modulated radiation therapy (IMRT) of the prostate only compared to additional irradiation of the pelvic lymphatic region.
For ten patients with localized prostate cancer, IMRT plans with a simultaneous integrated boost (SIB) were generated for treatment of the prostate only (plan-PO) and for additional treatment of the pelvic lymph nodes (plan-WP). In plan-PO, doses of 60 Gy and 74 Gy (33 fractions) were prescribed to the seminal vesicles and to the prostate, respectively. Three plans-WP were generated with prescription doses of 46 Gy, 50.4 Gy and 54 Gy to the pelvic target volume; doses to the prostate and seminal vesicles were identical to plan-PO. The risk of rectal, bladder and small bowel toxicity was estimated based on NTCP calculations.
Doses to the prostate were not significantly different between plan-PO and plan-WP and doses to the pelvic lymph nodes were as planned. Plan-WP resulted in increased doses to the rectum in the low-dose region ≤ 30 Gy, only, no difference was observed in the mid and high-dose region. Normal tissue complication probability (NTCP) for late rectal toxicity ranged between 5% and 8% with no significant difference between plan-PO and plan-WP. NTCP for late bladder toxicity was less than 1% for both plan-PO and plan-WP. The risk of small bowel toxicity was moderately increased for plan-WP.
This retrospective planning study predicted similar risks of rectal, bladder and small bowel toxicity for IMRT treatment of the prostate only and for additional treatment of the pelvic lymph nodes.
PMCID: PMC2253547  PMID: 18190681
6.  Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells 
BMC Cancer  2007;7:213.
Hypoxia-inducible factor-1 (HIF-1) overexpression has been linked to tumor progression and poor prognosis. We investigated whether targeting of HIF-1 using chetomin, a disrupter of the interaction of HIF-1 with the transcriptional coactivator p300, influences the radiosensitivity of hypoxic HT 1080 human fibrosarcoma cells.
Optimal dose of chetomin was determined by EGFP-HRE gene reporter assay in stably transfected HT 1080 cells. Cells were assayed for expression of the hypoxia-inducible genes carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) by RT-PCR and for clonogenic survival after irradiation with 2, 5 or 10 Gy, under normoxic or hypoxic (0.1% O2, 12 h) conditions in the presence or absence of chetomin (150 nM, 12 h, pre-treatment of 4 h).
Chetomin treatment significantly reduced CA9 and VEGF mRNA expression in hypoxic cells to 44.4 ± 7.2% and 39.6 ± 16.0%, respectively, of untreated hypoxic controls. Chetomin clearly reduced the modified oxygen enhancement ratio (OER') compared to untreated cells, from 2.02 to 1.27, from 1.86 to 1.22 and from 1.49 to 1.06 at the 50%, 37% and 10% clonogenic survival levels, respectively.
HIF-1 inhibition by chetomin effectively reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro.
PMCID: PMC2200672  PMID: 17999771
7.  Distinct effects of rectum delineation methods in 3D-confromal vs. IMRT treatment planning of prostate cancer 
The dose distribution to the rectum, delineated as solid organ, rectal wall and rectal surface, in 3D conformal (3D-CRT) and intensity-modulated radiotherapy treatment (IMRT) planning for localized prostate cancer was evaluated.
Materials and methods
In a retrospective planning study 3-field, 4-field and IMRT treatment plans were analyzed for ten patients with localized prostate cancer. The dose to the rectum was evaluated based on dose-volume histograms of 1) the entire rectal volume (DVH) 2) manually delineated rectal wall (DWH) 3) rectal wall with 3 mm wall thickness (DWH3) 4) and the rectal surface (DSH). The influence of the rectal filling and of the seminal vesicles' anatomy on these dose parameters was investigated. A literature review of the dose-volume relationship for late rectal toxicity was conducted.
In 3D-CRT (3-field and 4-field) the dose parameters differed most in the mid-dose region: the DWH showed significantly lower doses to the rectum (8.7% ± 4.2%) compared to the DWH3 and the DSH. In IMRT the differences between dose parameters were larger in comparison with 3D-CRT. Differences were statistically significant between DVH and all other dose parameters and between DWH and DSH. Mean doses were increased by 23.6% ± 8.7% in the DSH compared to the DVH in the mid-dose region. Furthermore, both the rectal filling and the anatomy of the seminal vesicles influenced the relationship between the dose parameters: a significant correlation of the difference between DVH and DWH and the rectal volume was seen in IMRT treatment.
The method of delineating the rectum significantly influenced the dose representation in the dose-volume histogram. This effect was pronounced in IMRT treatment planning compared to 3D-CRT. For integration of dose-volume parameters from the literature into clinical practice these results have to be considered.
PMCID: PMC1570470  PMID: 16956403

Results 1-7 (7)