Maria Thor

Deformable image registration for contour propagation from CT to cone-beam CT scans in radiotherapy of prostate cancer

Abstract Background and purpose. Daily organ motion occurring during the course of radiotherapy in the pelvic region leads to uncertainties in the doses delivered to the tumour and the organs at risk. Motion patterns include both volume and shape changes, calling for deformable image registration (DIR), in approaches involving dose accumulation and adaptation. In this study, we tested the performance of a DIR application for contour propagation from the treatment planning computed tomography (pCT) to repeat cone-beam CTs (CBCTs) for a set of prostate cancer patients. Material and methods. The prostate, rectum and bladder were delineated in the pCT and in six to eight repeat CBCTs for each of five patients. The pCT contours were propagated onto the corresponding CBCT using the Multi-modality Image Registration and Segmentation application, resulting in 36 registrations. Prior to the DIR, a rigid registration was performed. The algorithm used for the DIR was based on a ‘demons’ algorithm and the performance of it was examined quantitatively using the Dice similarity coefficient (DSC) and qualitatively as visual slice-by-slice scoring by a radiation oncologist grading the deviations in shape and/or distance relative to the anatomy. Results. The average DSC (range) for the DIR over all scans and patients was 0.80 (0.65–0.87) for prostate, 0.77 (0.63–0.87) for rectum and 0.73 (0.34–0.91) for bladder, while the corresponding DSCs for the rigid registrations were 0.77 (0.65–0.86), 0.71 (0.55–0.82) and 0.64 (0.33–0.87). The percentage of propagated contours of good/acceptable quality was 45% for prostate; 20% for rectum and 33% for bladder. For the bladder, there was an association between the average DSC and the different scores of the qualitative evaluation. Conclusions. DIR improved the performance of pelvic organ contour propagation from the pCT to CBCTs as compared to rigid registration only. Still, a large fraction of the propagated rectum and bladder contours were unacceptable. The image quality of the CBCTs was sub-optimal and the usability of CBCTs for dose accumulation and adaptation purposes is therefore likely to benefit from improved image quality and improvements of the DIR algorithm.

Prediction of rectum and bladder morbidity following radiotherapy of prostate cancer based on motion-inclusive dose distributions.

BACKGROUND AND PURPOSE In radiotherapy (RT) of prostate cancer the key organs at risk (ORs) - the rectum and the bladder - display considerable motion, which may influence the dose/volume parameters predicting for morbidity. In this study we compare motion-inclusive doses to planned doses for the rectum and bladder and explore their associations with prospectively recorded morbidity. MATERIALS AND METHODS The study included 38 prostate cancer patients treated with hypo-fractionated image-guided intensity-modulated RT that had an average of nine repeat CT scans acquired during treatment. These scans were registered to the respective treatment planning CT (pCT) followed by a new dose calculation from which motion-inclusive dose distributions were derived. The pCT volumes, the treatment course averaged volumes as well as the planned and motion-inclusive doses were associated with acute and late morbidity (morbidity cut-off: ≥ Grade 2). RESULTS Acute rectal morbidity (observed in 29% of cases) was significantly associated with both smaller treatment course averaged rectal volumes (population median: 75 vs. 94 cm(3)) and the motion-inclusive volume receiving doses close to the prescription dose (2 Gy-equivalent dose of 76 Gy). CONCLUSION Variation in rectum and bladder volumes leads to deviations between planned and delivered dose/volume parameters that should be accounted for to improve the ability to predict morbidity following RT.

Relationships between dose to the gastro-intestinal tract and patient-reported symptom domains after radiotherapy for localized prostate cancer.

ABSTRACT Background. Gastrointestinal (GI) morbidity after radiotherapy (RT) for prostate cancer is typically addressed by studying specific single symptoms. The aim of this study was to explore the interplay between domains of patient- reported outcomes (PROs) on GI morbidity, and to what extent these are explained by RT dose to the GI tract. Material and methods. The study included men from two Scandinavian studies (N = 211/277) who had undergone primary external beam radiotherapy (EBRT) for localized prostate cancer to 70–78 Gy (2 Gy/fraction). Factor analysis was applied to previously identified PRO-based symptom domains from two study-specific questionnaires. Number of questions: 43; median time to follow-up: 3.6–6.4 years) and dose-response outcome variables were defined from these domains. Dose/volume parameters of the anal sphincter (AS) or the rectum were tested as predictors for each outcome variable using logistic regression with 10-fold cross-validation. Performance was assessed using area under the receiver operating characteristic curve (Az) and model frequency. Results. Outcome variables from Defecation urgency (number of symptoms: 2–3), Fecal leakage (4–6), Mucous (4), and Pain (3–6) were defined. In both cohorts, intermediate rectal doses predicted Defecation urgency (mean Az: 0.53–0.54; Frequency: 70–75%), and near minimum and low AS doses predicted Fecal leakage (mean Az: 0.63–0.67; Frequency: 83–99%). In one cohort, high AS doses predicted Mucous (mean Az: 0.54; Frequency: 96%), whereas in the other, low AS doses and intermediate rectal doses predicted Pain (mean Az: 0.69; Frequency: 28–82%). Conclusion. We have demonstrated that Defecation urgency, Fecal leakage, Mucous, and Pain following primary EBRT for localized prostate cancer primarily are predicted by intermediate rectal doses, low AS doses, high AS doses, or a combination of low AS and intermediate rectal doses, respectively. This suggests that there is a domain-specific dose-response for the GI tract. To reduce risk of GI morbidity, dose distributions of both the AS region and the rectum should, therefore, be considered when prescribing prostate cancer RT.

Dose/volume-based evaluation of the accuracy of deformable image registration for the rectum and bladder

Abstract Background and purpose. Deformable image registration (DIR) is a key component of image-guided and adaptive strategies in radiotherapy. DIR based on image intensities alone is promising for online applications, but is challenged in regions with low intensity gradients. In this study we have investigated the performance of intensity- based DIR applied to contour propagation of the rectum and bladder, focusing on the consequences in terms of dose/volume parameters. Material and methods. The rectum and bladder volumes were delineated in the planning computed tomography (pCT) scan and in 8–9 repeat CTs (Vmanual) for nine prostate cancer patients. The volumes from the pCT were propagated onto the repeat CTs using intensity-based DIR (Vprop). Dose/volume parameters for Vmanual and Vprop were derived by dose re-calculations following rigid registration on prostate fiducials. Linear regression was used to identify qualitative and quantitative volumetric measures of the DIR performance being associated with the differences in dose/volume parameters. Results. The median differences in dose/volume parameters assessed for Vprop and Vmanual were modest, but individual differences ˜ 7 Gy were seen. The observed differences in dose/volume parameters showed strong correlations to the measures of the DIR performance as well as with the volume variations, most pronounced for the rectum (R2 = 0.63–0.85; p ≤ 0.05). Conclusion. Limitations in the intensity-based DIR algorithm resulted in large individual differences in dose/volume parameters between propagated and manually segmented volumes, which were correlated with volumetric measures of the DIR performance.

Statistical simulations to estimate motion-inclusive dose-volume histograms for prediction of rectal morbidity following radiotherapy.

Abstract Background and purpose. Internal organ motion over a course of radiotherapy (RT) leads to uncertainties in the actual delivered dose distributions. In studies predicting RT morbidity, the single estimate of the delivered dose provided by the treatment planning computed tomography (pCT) is typically assumed to be representative of the dose distribution throughout the course of RT. In this paper, a simple model for describing organ motion is introduced, and is associated to late rectal morbidity data, with the aim of improving morbidity prediction. Material and methods. Organ motion was described by normally distributed translational motion, with its magnitude characterised by the standard deviation (SD) of this distribution. Simulations of both isotropic and anisotropic (anterior-posterior only) motion patterns were performed, as were random, systematic or combined random and systematic motion. The associations between late rectal morbidity and motion-inclusive delivered dose-volume histograms (dDVHs) were quantified using Spearmans rank correlation coefficient (Rs) in a series of 232 prostate cancer patients, and were compared to the associations obtained with the static/planned DVH (pDVH). Results. For both isotropic and anisotropic motion, different associations with rectal morbidity were seen with the dDVHs relative to the pDVHs. The differences were most pronounced in the mid-dose region (40–60 Gy). The associations were dependent on the applied motion patterns, with the strongest association with morbidity obtained by applying random motion with an SD in the range 0.2–0.8 cm. Conclusion. In this study we have introduced a simple model for describing organ motion occurring during RT. Differing and, for some cases, stronger dose-volume dependencies were found between the motion-inclusive dose distributions and rectal morbidity as compared to the associations with the planned dose distributions. This indicates that rectal organ motion during RT influences the efforts to model the risk of morbidity using planning distributions alone.

Dose/volume-response relations for rectal morbidity using planned and simulated motion-inclusive dose distributions.

BACKGROUND AND PURPOSE Many dose-limiting normal tissues in radiotherapy (RT) display considerable internal motion between fractions over a course of treatment, potentially reducing the appropriateness of using planned dose distributions to predict morbidity. Accounting explicitly for rectal motion could improve the predictive power of modelling rectal morbidity. To test this, we simulated the effect of motion in two cohorts. MATERIALS AND METHODS The included patients (232 and 159 cases) received RT for prostate cancer to 70 and 74 Gy. Motion-inclusive dose distributions were introduced as simulations of random or systematic motion to the planned dose distributions. Six rectal morbidity endpoints were analysed. A probit model using the QUANTEC recommended parameters was also applied to the cohorts. RESULTS The differences in associations using the planned over the motion-inclusive dose distributions were modest. Statistically significant associations were obtained with four of the endpoints, mainly at high doses (55-70 Gy), using both the planned and the motion-inclusive dose distributions, primarily when simulating random motion. The strongest associations were observed for GI toxicity and rectal bleeding (Rs=0.12-0.21; Rs=0.11-0.20). Applying the probit model, significant associations were found for tenesmus and rectal bleeding (Rs=0.13, p=0.02). CONCLUSION Equally strong associations with rectal morbidity were observed at high doses (>55 Gy), for the planned and the simulated dose distributions including in particular random rectal motion. Future studies should explore patient-specific descriptions of rectal motion to achieve improved predictive power.

Rectum motion and morbidity prediction: Improving correlation between late morbidity and DVH parameters through use of rectum planning organ at risk volumes

Abstract Background and purpose. The rectum is a major dose-limiting organ at risk (OR) in radiotherapy (RT) of prostate cancer. Methods to predict adverse effects in the rectum are therefore important but their precision often limited, not the least by the internal motion of this organ. In this study late rectal morbidity is investigated in relation to the internal motion of the rectum by applying the ‘Planning organ at Risk Volume’ (PRV) concept. Materials and methods: Late rectal morbidity was analysed in 242 prostate cancer patients treated to 70 Gy with conformal RT to either the prostate, the prostate and seminal vesicles or the whole pelvis (initial 50 Gy only). Late rectal morbidity was classified by the late gastro-intestinal (GI) RTOG toxicity scoring system. Cumulative dose-volume histograms (DVHs) were derived for the rectum OR and six rectum PRVs i.e. the OR expanded with six different margins (narrow/intermediate/wide in anterior direction or in both anterior and posterior direction). The difference in rectum dose-volume parameters between patients with Grade 0–1 vs. Grade 2 or higher morbidity was investigated by logistic regression and permutation tests. Results: Late Grade 2 or higher morbidity was observed in 25 of 242 (10%) patients. The logistic regression analysis and the permutation tests reached significance (p ≤ 0.05) for only one dose level of the rectum OR (40 Gy). For the PRVs, several dose levels were found to be significant (p-value range: 0.01–0.046), most pronounced for the PRV with narrow margins of 6 mm anterior and 5 mm posterior with five intermediate (38–42 Gy) and ten high (62–71 Gy) dose levels. Conclusions: The statistical methods applied displayed consistently a small though significant difference in DVH parameters between patients with vs. without Grade 2 or higher late rectal morbidity for intermediate and high dose levels. The difference became most evident when using a PRV with narrow margins.

Urinary bladder dose–response relationships for patient-reported genitourinary morbidity domains following prostate cancer radiotherapy

BACKGROUND AND PURPOSE Radiotherapy (RT) induced genitourinary (GU) morbidity is typically assessed by physicians as single symptoms or aggregated scores including symptoms from various domains. Here we apply a method to group patient-reported GU symptoms after RT for localized prostate cancer based on their interplay, and study how these relate to urinary bladder dose. MATERIALS AND METHODS Data were taken from two Scandinavian studies (N=207/276) including men treated with external-beam RT (EBRT) to 78/70Gy (2Gy/fraction; median time-to-follow-up: 3.6-6.4y). Within and across cohorts, bladder dose-volume parameters were tested as predictors for GU symptom domains identified from two study-specific questionnaires (35 questions on frequency, incontinence, obstruction, pain, urgency, and sensory symptoms) using univariate and multivariate logistic regression analysis (MVA) with 10-fold cross-validation. Performance was evaluated using Area Under the Receiver Operating Characteristic Curve (Az). RESULTS For the identified Incontinence (2-5 symptoms), Obstruction (3-5 symptoms), and Urgency (2-7 symptoms) domains, MVA demonstrated that bladder doses close to the prescription doses were the strongest predictors for Obstruction (Az: 0.53-0.57) and Urgency (Az: 0.60). For Obstruction, performance increased for the across cohort analysis (Az: 0.61-0.64). CONCLUSIONS Our identified patient-reported GU symptom domains suggest that high urinary bladder doses, and increased focus on both obstruction and urgency is likely to further add to the understanding of GU tract RT responses.

Evaluation of an application for intensity-based deformable image registration and dose accumulation in radiotherapy

Abstract Background. Methods to accurately accumulate doses in radiotherapy (RT) are important for tumour and normal tissues being influenced by geometric uncertainties. The purpose of this study was to investigate a pre-release deformable image registration (DIR)-based dose accumulation application, in the setting of prostate RT. Material and methods. Initially accumulated bladder and prostate doses were assessed (based on 8–9 repeat CT scans/patient) for nine prostate cancer patients using an intensity-based DIR and dose accumulation algorithm as provided by the Dynamic Adaptive Radiation Therapy (DART) software. The accumulated bladder and prostate dose-volume histograms (DVHs) were compared on a range of parameters (paired Wilcoxon signed-rank test, 5% significance level) to DVHs derived using an in-house developed dose accumulation method based on biomechanical, contour-driven DIR (SurfaceRegistration). Finally, both these accumulated dose distributions were compared to the ‘static’ DVH, assessed from the planning CT. Results. Over the population, doses accumulated with DART were overall lower than those from SurfaceRegistration (p < 0.05: D2%, gEUD and NTCP (bladder); Dmin (prostate)). The magnitude of these differences peaked for the bladder gEUD with a population median of 47 Gy for DART versus 57 Gy for SurfaceRegistration. Across the ten bladder dose/volume parameters investigated, the most pronounced individual differences were observed between the ‘accumulated’ DVHs and the ‘static’ DVHs, with deviations in mean dose up to 22 Gy. Conclusion. Substantial and significant differences were observed in the dose distributions between the two investigated DIR-based dose accumulation applications. The most pronounced individual differences were seen for the bladder and relative to the planned dose distribution, encouraging the use of repeat imaging data in RT planning and evaluation for this organ.

An image-based method to quantify biomechanical properties of the rectum in radiotherapy of prostate cancer

ABSTRACT Background. Gastrointestinal morbidity after radiotherapy (RT) for prostate cancer may be related to the biomechanical properties of the rectum. In this study we present a magnetic resonance imaging (MRI)-based method to quantitate the thickness and elasticity of the rectal wall in prostate cancer patients treated with RT. Material and methods. Four patients previously treated with RT for prostate cancer underwent an MRI session with stepwise rectal bag deflation (from a maximum tolerable volume to 0 ml, in 50 ml steps), with a probe inserted inside the bag to monitor the internal rectal pressure. MRIs were acquired using Dixon sequences (4 mm axial slice thickness) at each deflation step. Rectal walls were defined from the recto-sigmoid junction to 3 cm above the anal canal as the space between the inner and outer wall surfaces. The wall thickness was determined and biomechanical properties (strain and stress) were calculated from the pressure measurements and the MRI-segmented rectal walls. Results. The integral rectal pressure varied for the maximum tolerable volume (range 150–250 ml) across patients and ranged from 1.3 to 4.0 kPa (SD = 1.2 kPa). Wall thickness was found to vary between patients and also across different rectum segments, with a mean (SD) thickness for the different segments at the 50 ml distension volume of 1.8–4.0 (0.6) mm. Stress showed larger variation than strain, with mean (SD) values for the different segments ranging between 1.5 and 7.0 (1.5) kPa. Conclusion. We have developed a method to quantify biomechanical properties of the rectal wall. The resulting rectal wall thickness, strain and stress differed between patients, as well as across different rectal wall sections. These findings could provide guidance in future predictive outcome modelling in order to better understand the rectal dose-volume response relationship.