Normal tissue complication probability models for severe acute radiological lung injury after radiotherapy for lung cancer.

PURPOSE: To derive Normal Tissue Complication Probability (NTCP) models for severe patterns of early radiological radiation-induced lung injury (RRLI) in patients treated with radiotherapy (RT) for lung tumors. Second, derive threshold doses and optimal doses for prediction of RRLI to be used in differential diagnosis of tumor recurrence from RRLI during follow-up. METHODS AND MATERIALS: Lyman-EUD (LEUD), Logit-EUD (LogEUD), relative seriality (RS) and critical volume (CV) NTCP models, with DVH corrected for fraction size, were used to model the presence of severe early RRLI in follow-up CTs. The models parameters, including α/ß, were determined by fitting data from forty-five patients treated with IMRT for lung cancer. Models were assessed using Akaike information criterion (AIC) and area under receiver operating characteristic curve (AUC). Threshold doses for risk of RRLI and doses corresponding to the optimal point of the receiver operating characteristic (ROC) curve were determined. RESULTS: The α/ßs obtained with different models were 2.7-3.2 Gy. The thresholds and optimal doses curves were EUDs of 3.2-7.8 Gy and 15.2-18.1 Gy with LEUD, LogEUD and RS models, and µd of 0.013 and 0.071 with the CV model. NTCP models had AUCs significantly higher than 0.5. Occurrence and severity of RRLI were correlated with patients' values of EUD and µd. CONCLUSIONS: The models and dose levels derived can be used in differential diagnosis of tumor recurrence from RRLI in patients treated with RT. Cross validation is needed to prove prediction performance of the model outside the dataset from which it was derived.

Atlas-based functional radiosurgery: early results.

Functional disorders of the brain, such as dystonia and neuropathic pain, may respond poorly to medical therapy. Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and the centromedian nucleus of the thalamus (CMN) may alleviate dystonia and neuropathic pain, respectively. A noninvasive alternative to DBS is radiosurgical ablation [internal pallidotomy (IP) and medial thalamotomy (MT)]. The main technical limitation of radiosurgery is that targets are selected only on the basis of MRI anatomy, without electrophysiological confirmation. This means that, to be feasible, image-based targeting must be highly accurate and reproducible. Here, we report on the feasibility of an atlas-based approach to targeting for functional radiosurgery. In this method, masks of the GPi, CMN, and medio-dorsal nucleus were nonrigidly registered to patients' T1-weighted MRI (T1w-MRI) and superimposed on patients' T2-weighted MRI (T2w-MRI). Radiosurgical targets were identified on the T2w-MRI registered to the planning CT by an expert functional neurosurgeon. To assess its feasibility, two patients were treated with the CyberKnife using this method of targeting; a patient with dystonia received an IP (120 Gy prescribed to the 65% isodose) and a patient with neuropathic pain received a MT (120 Gy to the 77% isodose). Six months after treatment, T2w-MRIs and contrast-enhanced T1w-MRIs showed edematous regions around the lesions; target placements were reevaluated by DW-MRIs. At 12 months post-treatment steroids for radiation-induced edema and medications for dystonia and neuropathic pain were suppressed. Both patients experienced significant relief from pain and dystonia-related problems. Fifteen months after treatment edema had disappeared. Thus, this work shows promising feasibility of atlas-based functional radiosurgery to improve patient condition. Further investigations are indicated for optimizing treatment dose.

Development and validation of a smoothing-splines-based correction method for improving the analysis of CEST-MR images.

Chemical exchange saturation transfer (CEST) imaging is an emerging MRI technique relying on the use of endogenous or exogenous molecules containing exchangeable proton pools. The heterogeneity of the water resonance frequency offset plays a key role in the occurrence of artifacts in CEST-MR images. To limit this drawback, a new smoothing-splines-based method for fitting and correcting Z-spectra in order to compensate for low signal-to-noise ratio (SNR) without any a priori model was developed. Global and local voxel-by-voxel Z-spectra were interpolated by smoothing splines with smoothing terms aimed at suppressing noise. Thus, a map of the water frequency offset ('zero' map) was used to correctly calculate the saturation transfer (ST) for each voxel. Simulations were performed to compare the method to polynomials and zero-only-corrected splines on the basis of SNR improvement. In vitro acquisitions of capillaries containing solutions of LIPOCEST agents at different concentrations were performed to experimentally validate the results from simulations. Additionally, ex vivo investigations of bovine muscle mass injected with LIPOCEST agents were performed as a function of increasing pulse power. The results from simulations and experiments highlighted the importance of a proper 'zero' correction (15% decrease of fictitious CEST signal in phantoms and ex vivo preparations) and proved the method to be more accurate compared with the previously published ones, often providing a SNR higher than 5 in different simulated and experimentally noisy conditions. In conclusion, the proposed method offers an accurate tool in CEST investigation.

Use of motion tracking in stereotactic body radiotherapy: Evaluation of uncertainty in off-target dose distribution and optimization strategies.

Spatial accuracy in extracranial radiosurgery is affected by organ motion. Motion tracking systems may be able to avoid PTV enlargement while preserving treatment times, however special attention is needed when fiducial markers are used to identify the target can move with respect to organs at risk (OARs). Ten patients treated by means of the Synchrony system were taken into account. Sparing of irradiated volume and of complication probability were estimated by calculating treatment plans with a motion tracking system (Cyberknife Synchrony, Sunnyvale, CA, USA) and a PTV-enlargement strategy for ten patients. Six patients were also evaluated for possible inaccuracy of estimation of dose to OARs due to relative movement between PTV and OAR during respiration. Dose volume histograms (DVH) and Equivalent Uniform Dose (EUD) were calculated for the organs at risk. In the cases for which the target moved closer to the OAR (three cases of six), a small but significant increase was detected in the DVH and EUD of the OAR. In three other cases no significant variation was detected. Mean reduction in PTV volume was 38% for liver cases, 44% for lung cases and 8.5% for pancreas cases. NTCP for liver reduced from 23.1 to 14.5% on average, for lung it reduced from 2.5 to 0.1% on average. Significant uncertainty may arise from the use of a motion-tracking device in determination of dose to organs at risk due to the relative motion between PTV and OAR. However, it is possible to limit this uncertainty. The breathing phase in which the OAR is closer to the PTV should be selected for planning. A full understanding of the dose distribution would only be possible by means of a complete 4D-CT representation.

Preliminary study on the use of nonrigid registration for thoraco-abdominal radiosurgery.

The inclusion of organ deformation and movement in radiosurgery treatment planning is of increasing importance as research and clinical applications begin to take into consideration the effects of physiological processes, like breathing, on the shape and position of lesions. In this scenario, the challenge is to localize the target in toto (not only by means of marker sampling) and to calculate the dose distribution as the sum of all the contributions from the positions assumed by the target during the respiratory cycle. The aim of this work is to investigate the use of nonrigid registration for target tracking and dynamic treatment planning, i.e., treatment planning based not on one single CT scan but on multiple CT scans representative of the respiration. Twenty patients were CT scanned at end-inhale and end-exhale. An expert radiation oncologist identified the PTV in both examinations. The two CT data sets per patient were nonrigidly registered using a free-form deformation algorithm based on B-splines. The optimized objective function consisted of a weighted sum of a similarity criterion (Mutual Information) and a regularization factor which constrains the transformation to be locally rigid. Once the transformation was obtained and the registration validated, its parameters were applied to the target only. Finally, the deformed target was compared to the PTV delineated by the radiation oncologist in the other study. The results of this procedure show an agreement between the center of mass as well as volume of the target identified automatically by deformable registration and manually by the radiation oncologist. Moreover, obtained displacements were in agreement with body structure constraints and considerations usually accepted in radiation therapy practice. No significant influence of initial target volume on displacements was found. In conclusion, the proposed method seems to offer the possibility of using nonrigid registrations in radiosurgery treatment planning, even if more cases need to be investigated in order to give a statistical consistency to parameter setup and proposed considerations.

CT-3D rotational angiography automatic registration: a sensitivity analysis.

Preprocessing, binning and dataset subsampling are investigated with regard to simultaneous maximisation of the speed, accuracy and robustness of CT-3D rotational angiography (3DRA) registration. Clinical diagnosis and treatment can both take advantage of this integration, because 3DRA allows the shape of vessel structures to be evaluated three-dimensionally with respect to standard 2D projective angiography. The method for optimising preprocessing, binning and subsampling consisted of independent variation of the corresponding parameters to maximise robustness and speed while maintaining subvoxel accuracy; the latter was computed as the sum of the mean squared errors initially present in the registrations with the errors relative to both binning and subsampling. The results suggest the choice of 256 bins, steps between 14 mm (coarse optimisation) and 2.5 mm (fine optimisation) and bone segmentation by threshold, for binning, subsampling and preprocessing, respectively. The application of this parameter set-up to 50 CT-3DRA registrations resulted in a saving, on average, of 40% of the time with respect to the method previously used, while registration error was maintained within 2 mm (1.97 mm, 90% confidence interval) and robustness was increased, so that no manual initial realignment was needed in 48 registrations. Validation by the registration of images acquired for a head phantom showed subvoxel residual errors. In conclusion, the proposed procedure can be considered a satisfactory strategy to optimise CT-3DRA registration.