A.G. Zolnay

Treatment simulations with a statistical deformable motion model to evaluate margins for multiple targets in radiotherapy for high-risk prostate cancer.

BACKGROUND AND PURPOSEnDeformation and correlated target motion remain challenges for margin recipes in radiotherapy (RT). This study presents a statistical deformable motion model for multiple targets and applies it to margin evaluations for locally advanced prostate cancer i.e. RT of the prostate (CTV-p), seminal vesicles (CTV-sv) and pelvic lymph nodes (CTV-ln).nnnMATERIAL AND METHODSnThe 19 patients included in this study, all had 7-10 repeat CT-scans available that were rigidly aligned with the planning CT-scan using intra-prostatic implanted markers, followed by deformable registrations. The displacement vectors from the deformable registrations were used to create patient-specific statistical motion models. The models were applied in treatment simulations to determine probabilities for adequate target coverage, e.g. by establishing distributions of the accumulated dose to 99% of the target volumes (D99) for various CTV-PTV expansions in the planning-CTs.nnnRESULTSnThe method allowed for estimation of the expected accumulated dose and its variance of different DVH parameters for each patient. Simulations of inter-fractional motion resulted in 7, 10, and 18 patients with an average D99 >95% of the prescribed dose for CTV-p expansions of 3mm, 4mm and 5mm, respectively. For CTV-sv and CTV-ln, expansions of 3mm, 5mm and 7 mm resulted in 1, 11 and 15 vs. 8, 18 and 18 patients respectively with an average D99 >95% of the prescription.nnnCONCLUSIONSnTreatment simulations of target motion revealed large individual differences in accumulated dose mainly for CTV-sv, demanding the largest margins whereas those required for CTV-p and CTV-ln were comparable.

Control over structure‐specific flexibility improves anatomical accuracy for point‐based deformable registration in bladder cancer radiotherapy

PURPOSEnFuture developments in image guided adaptive radiotherapy (IGART) for bladder cancer require accurate deformable image registration techniques for the precise assessment of tumor and bladder motion and deformation that occur as a result of large bladder volume changes during the course of radiotherapy treatment. The aim was to employ an extended version of a point-based deformable registration algorithm that allows control over tissue-specific flexibility in combination with the authors unique patient dataset, in order to overcome two major challenges of bladder cancer registration, i.e., the difficulty in accounting for the difference in flexibility between the bladder wall and tumor and the lack of visible anatomical landmarks for validation.nnnMETHODSnThe registration algorithm used in the current study is an extension of the symmetric-thin plate splines-robust point matching (S-TPS-RPM) algorithm, a symmetric feature-based registration method. The S-TPS-RPM algorithm has been previously extended to allow control over the degree of flexibility of different structures via a weight parameter. The extended weighted S-TPS-RPM algorithm was tested and validated on CT data (planning- and four to five repeat-CTs) of five urinary bladder cancer patients who received lipiodol injections before radiotherapy. The performance of the weighted S-TPS-RPM method, applied to bladder and tumor structures simultaneously, was compared with a previous version of the S-TPS-RPM algorithm applied to bladder wall structure alone and with a simultaneous nonweighted S-TPS-RPM registration of the bladder and tumor structures. Performance was assessed in terms of anatomical and geometric accuracy. The anatomical accuracy was calculated as the residual distance error (RDE) of the lipiodol markers and the geometric accuracy was determined by the surface distance, surface coverage, and inverse consistency errors. Optimal parameter values for the flexibility and bladder weight parameters were determined for the weighted S-TPS-RPM.nnnRESULTSnThe weighted S-TPS-RPM registration algorithm with optimal parameters significantly improved the anatomical accuracy as compared to S-TPS-RPM registration of the bladder alone and reduced the range of the anatomical errors by half as compared with the simultaneous nonweighted S-TPS-RPM registration of the bladder and tumor structures. The weighted algorithm reduced the RDE range of lipiodol markers from 0.9-14 mm after rigid bone match to 0.9-4.0 mm, compared to a range of 1.1-9.1 mm with S-TPS-RPM of bladder alone and 0.9-9.4 mm for simultaneous nonweighted registration. All registration methods resulted in good geometric accuracy on the bladder; average error values were all below 1.2 mm.nnnCONCLUSIONSnThe weighted S-TPS-RPM registration algorithm with additional weight parameter allowed indirect control over structure-specific flexibility in multistructure registrations of bladder and bladder tumor, enabling anatomically coherent registrations. The availability of an anatomically validated deformable registration method opens up the horizon for improvements in IGART for bladder cancer.

Quantification of intra-fraction changes during radiotherapy of cervical cancer assessed with pre- and post-fraction Cone Beam CT scans

BACKGROUND AND PURPOSEnWith the introduction of Intensity Modulated Radiotherapy (IMRT) and image-guided plan-of-the-day strategies, the treatment of cervical cancer has become more sensitive to intra-fraction uncertainties. In this study we quantified intra-fraction changes in cervix-uterus shape, bladder and rectum filling, and patient setup using pre- and post-fraction CBCT scans.nnnMATERIALS AND METHODSnA total of 632 CBCT scans were analyzed for 16 patients with large tip-of-uterus displacement (>2.5 cm) measured in an empty and full bladder CT scan. In all scans, the bladder, cervix-uterus, and rectum were delineated. For rectum and bladder, intra-fraction volume changes were assessed. Systematic cervix-uterus intra-fraction displacements were obtained by non-rigidly aligning the pre-fraction cervix-uterus to that in the post-fraction CBCT. Intra-fraction patient setup changes were obtained by rigidly aligning pre- and post-CBCTs using the bony anatomy.nnnRESULTSnThe mean time between pre- and post-fraction CBCT scan was 20.8 min. The group-mean intra-fraction displacements averaged over the cervix-uterus were 0.1±1.4/1.8±1.5/-2.8±1.8 (LR/CC/AP) mm. The group-mean 5th and 95th percentile intra-fraction displacements were -2.3,2.1/-0.8,4.9/-5.8,0.5 (LR/CC/AP) mm. There was a significant correlation between bladder inflow rate and cervix-uterus motion (r=0.6 and p<0.01). Intra-fraction changes in patient setup were 1.3/0.4/0.6 and 1.4/1.0/1.1 mm (LR/CC/AP), for systematic and random changes, respectively.nnnCONCLUSIONnIntra-fraction cervix-uterus motion can be considerable and should be taken into account using appropriate PTV margins.

A quality control model that uses PTV-rectal distances to predict the lowest achievable rectum dose, improves IMRT planning for patients with prostate cancer

BACKGROUND AND PURPOSEnTo predict the lowest achievable rectum D35 for quality assurance of IMRT plans of prostate cancer patients.nnnMATERIALS AND METHODSnFor each of 24 patients from a database of 47 previously treated patients, the anatomy was compared to the anatomies of the other 46 to predict the minimal achievable rectum D35. The 24 patients were then replanned to obtain maximally reduced rectum D35. Next, the newly derived plans were added to the database to replace the original clinical plans, and new predictions of the lowest achievable rectum D35 were made.nnnRESULTSnAfter replanning, the rectum D35 reduced by 9.3 Gy±6.1 (average±1 SD; p<0.001) compared to the original plan. The first predictions of the rectum D35 were 4.8 Gy±4.2 (average±1 SD; p<0.001) too high when evaluated with the new plans. After updating the database, the replanned and newly predicted rectum D35 agreed within 0.1 Gy±2.8 (average±1 SD; p=0.89). The doses to the bladder, anus and femoral heads did not increase compared to the original plans.nnnCONCLUSIONSnFor individual prostate patients, the lowest achievable rectum D35 in IMRT planning can be accurately predicted from dose distributions of previously treated patients by quantitative comparison of patient anatomies. These predictions can be used to quantitatively assess the quality of IMRT plans.

Accurate CT∕MR vessel-guided nonrigid registration of largely deformed livers.

PURPOSEnComputer tomography (CT) scans are used for designing radiotherapy treatment plans. However, the tumor is often better visible in magnetic resonance (MR) images. For liver stereotactic body radiation therapy (SBRT), the planning CT scan is acquired while abdominal compression is applied to reduce tumor motion induced by breathing. However, diagnostic MR scans are acquired under voluntary breath-hold without the compression device. The resulting large differences in liver shape hinder the alignment of CT and MR image sets, which severely limits the integration of the information provided by these images. The purpose of the current study is to develop and validate a nonrigid registration method to align breath-hold MR images with abdominal-compressed CT images, using vessels that are automatically segmented within the liver.nnnMETHODSnContrast-enhanced MR and CT images of seven patients with liver cancer were used for this study. The registration method combines automatic vessel segmentation with an adapted version of thin-plate spline robust point matching. The vessel segmentation uses a multiscale vesselness measure, which allows vessels of various thicknesses to be segmented. The nonrigid registration is point-based, and progressively improves the correspondence and transformation between two point sets. Moreover, the nonrigid registration is capable of identifying and handling outliers (points with no counterpart in the other set). We took advantage of the strengths of both methods and created a multiscale registration algorithm. First, thick vessels are registered, then with each new iteration thinner vessels are included in the registration (strategy A). We compared strategy A to a straightforward approach where vessels of various diameters are segmented and subsequently registered (strategy B). To assess the transformation accuracy, residual distances were calculated for vessel bifurcations. For anatomical validation, residual distances were calculated for additional anatomical landmarks within the liver. To estimate the extent of deformation, the residual distances for the aforementioned anatomical points were calculated after rigid registration.nnnRESULTSnLiver deformations in the range of 2.8-10.7 mm were found after rigid registration of the CT and MR scans. Low residual distances for vessel bifurcations (average 1.6, range 1.3-1.9 mm) and additional anatomical landmarks (1.5, 1.1-2.4 mm) were found after nonrigid registration. A large amount of outliers were identified (25%-55%) caused by vessels present in only one of the image sets and false positives in the vesselness measure. The nonrigid registration was capable of handling these outliers as was demonstrated by the low residual distances. Both strategies yielded very similar results in registration accuracy, but strategy A was faster than strategy B (≥2.0 times).nnnCONCLUSIONSnAn accurate CT∕MR vessel-guided nonrigid registration for largely deformed livers was developed, tested, and validated. The method, combining vessel segmentation and point matching, was robust against differences in the segmented vessels. The authors conclude that nonrigid registration is required for accurate alignment of abdominal-compressed and uncompressed liver anatomy. Alignment of breath-hold MR and abdominal-compressed CT images can be used to improve tumor localization for liver SBRT.

Improving anatomical mapping of complexly deformed anatomy for external beam radiotherapy and brachytherapy dose accumulation in cervical cancer

PURPOSEnIn the treatment of cervical cancer, large anatomical deformations, caused by, e.g., tumor shrinkage, bladder and rectum filling changes, organ sliding, and the presence of the brachytherapy (BT) applicator, prohibit the accumulation of external beam radiotherapy (EBRT) and BT dose distributions. This work proposes a structure-wise registration with vector field integration (SW+VF) to map the largely deformed anatomies between EBRT and BT, paving the way for 3D dose accumulation between EBRT and BT.nnnMETHODSnT2w-MRIs acquired before EBRT and as a part of the MRI-guided BT procedure for 12 cervical cancer patients, along with the manual delineations of the bladder, cervix-uterus, and rectum-sigmoid, were used for this study. A rigid transformation was used to align the bony anatomy in the MRIs. The proposed SW+VF method starts by automatically segmenting features in the area surrounding the delineated organs. Then, each organ and feature pair is registered independently using a feature-based nonrigid registration algorithm developed in-house. Additionally, a background transformation is calculated to account for areas far from all organs and features. In order to obtain one transformation that can be used for dose accumulation, the organ-based, feature-based, and the background transformations are combined into one vector field using a weighted sum, where the contribution of each transformation can be directly controlled by its extent of influence (scope size). The optimal scope sizes for organ-based and feature-based transformations were found by an exhaustive analysis. The anatomical correctness of the mapping was independently validated by measuring the residual distances after transformation for delineated structures inside the cervix-uterus (inner anatomical correctness), and for anatomical landmarks outside the organs in the surrounding region (outer anatomical correctness). The results of the proposed method were compared with the results of the rigid transformation and nonrigid registration of all structures together (AST).nnnRESULTSnThe rigid transformation achieved a good global alignment (mean outer anatomical correctness of 4.3 mm) but failed to align the deformed organs (mean inner anatomical correctness of 22.4 mm). Conversely, the AST registration produced a reasonable alignment for the organs (6.3 mm) but not for the surrounding region (16.9 mm). SW+VF registration achieved the best results for both regions (3.5 and 3.4 mm for the inner and outer anatomical correctness, respectively). All differences were significant (p < 0.02, Wilcoxon rank sum test). Additionally, optimization of the scope sizes determined that the method was robust for a large range of scope size values.nnnCONCLUSIONSnThe novel SW+VF method improved the mapping of large and complex deformations observed between EBRT and BT for cervical cancer patients. Future studies that quantify the mapping error in terms of dose errors are required to test the clinical applicability of dose accumulation by the SW+VF method.

Adaptive radiotherapy in locally advanced prostate cancer using a statistical deformable motion model.

Abstract Daily treatment plan selection from a plan library is a major adaptive radiotherapy strategy to account for individual internal anatomy variations. This strategy depends on the initial input images being representative for the variations observed later in the treatment course. Focusing on locally advanced prostate cancer, our aim was to evaluate if residual motion of the prostate (CTV-p) and the elective targets (CTV-sv, CTV-ln) can be prospectively accounted for with a statistical deformable model based on images acquired in the initial part of treatment. Methods. Thirteen patients with locally advanced prostate cancer, each with 9–10 repeat CT scans, were included. Displacement vectors fields (DVF) obtained from contour-based deformable registration of delineations in the repeat- and planning CT scans were used to create patient-specific statistical motion models using principal component analysis (PCA). For each patient and CTV, four PCA-models were created: one with all 9–10 DVF as input in addition to models with only four, five or six DVFs as input. Simulations of target shapes from each PCA-model were used to calculate iso-coverage levels, which were converted to contours. The levels were analyzed for sensitivity and precision. Results. A union of the simulated shapes was able to cover at least 97%, 97% and 95% of the volumes of the evaluated CTV shapes for PCA-models using six, five and four DVFs as input, respectively. There was a decrease in sensitivity with higher iso-coverage levels, with a sharper decline for greater target movements. Apart from having the steepest decline in sensitivity, CTV-sv also displayed the greatest influence on the number of geometries used in the PCA-model. Conclusions. PCA-based simulations of residual motion derived from four to six DVFs as input could account for the majority of the target shapes present during the latter part of the treatment. CTV-sv displayed the greatest range in both sensitivity and precision.

What is the optimal number of library plans in ART for locally advanced cervical cancer

PURPOSEnLibrary-of-plans ART is used to manage daily anatomy changes in locally advanced cervical cancer. In our institute, the library contains 2 VMAT plans for patients with large cervix-uterus motion. Increasing this number could be beneficial for tissue sparing, but is burdensome while the dosimetric gain is yet unclear. This studys aim is to determine the optimal number of plans at an individual patient level.nnnMATERIAL AND METHODSnData of 14 treated patients were analyzed. Plan libraries were created containing 1-4 VMAT plans. Pre-treatment extent of uterus motion was defined by the 99th percentile of the Hausdorff distance (HD99). For dosimetric evaluations, OARs were contoured in daily CBCT scans, plan selection was simulated, and the V45Gy and V40Gy parameters were recorded.nnnRESULTSnModerate to strong correlations were found between HD99 and the volume of spared OARs. All patients benefitted from adding a 2nd plan, as is the clinical practice. For patients with a HD99 between 30 and 50mm, a 3-plan library reduced the composite V40Gy with 11-21ml compared to a 2-plan library.nnnCONCLUSIONnPatients with large uterus motion (HD99>30mm) would benefit from an extension of the plan library to 3. HD99 is an easy-to-implement criteria to select those patients pre-treatment.

Statistical motion modelling for robust evaluation of clinically delivered accumulated dose distributions after curative radiotherapy of locally advanced prostate cancer

BACKGROUND AND PURPOSEnPlanned doses are used as surrogate for the actually delivered dose in radiotherapy. We have estimated the delivered dose in a dose-escalation trial of locally advanced prostate cancer by statistical dose-accumulation and by DVH-summation, and compared to planned dose.nnnMATERIALS AND METHODnPrescribed dose-escalation to the prostate was 67.5u202fGy/25fr., corresponding to 81GyEQD2 assuming α/βu202f=u202f1.5. The 21 patients had three targets (i.e. CTV67.5u202f+u202f2u202fmm, CTV60u202f+u202f5u202fmm, CTV50u202f+u202f10u202fmm) irradiated by a simultaneous-integrated-boost technique. Analysis was based on 213 CT scans and 5-years of follow-up. For statistical dose-accumulation, we modelled 10000 possible treatment courses based on planned dose and deformation-vector-fields from contour-based registration. For DVH-summation we recalculated dose on repeat-CTs and estimated median D98%/EUD. Groups with/without disease recurrence were compared.nnnRESULTSnDiscrepancies between planned and accumulated dose were mostly seen for CTV67.5, where under-dosage was found at different locations in the prostate in 12/21 patients. Delivered dose-escalation (D98%) was on average 73.9GyEQD2 (range: 68.3-78.7GyEQD2). No significant difference in accumulated-D98% was found in patients with (nu202f=u202f8) and without (nu202f=u202f13) recurrence (pu202f>u202f0.05). Average D98%/EUD with statistical dose-accumulation vs DVH-summation was significantly different in CTV60, CTV50, rectum and bladder but not in CTV67.5.nnnCONCLUSIONnThe planned dose escalation was not received by more than half-of-the patients. Robustness of the prostate target (CTV67.5) should therefore be better prioritized in these patients given the low toxicity profile. Estimates of delivered dose were less conservative for dose-accumulation due to interaction of random organ motion with the dose matrix.

OC-0546: Intra-fraction motion in Plan-of-the-Day IMRT for cervical cancer assessed by pre- and post-fraction CBCT scans

Purpose/Objective: In our institute, cervical cancer patients are treated with a library-based Plan-of-the-Day (PotD) protocol. In this protocol an in-room Cone Beam CT (CBCT) scan acquired just before dose delivery is used to select the treatment plan that is best fitting the observed anatomy. However, treatment accuracy may be compromised by shape and position changes of the cervix-uterus resulting from intra-fractional filling of the bladder and rectum, and by intra-fraction variations in patient setup. The purpose of this study is to quantify these uncertainties using preand postfraction acquired CBCT scans. Materials and Methods: Intra-fraction uncertainties were evaluated for 16 cervical cancer patients with a tip-of-uterus displacement larger than 2.5 cm as measured in an empty and full bladder planning CT scan. The treatment protocol includes a post-fraction CBCT to verify target coverage after dose delivery. In 316 preand post-fraction CBCT scans, the bladder, cervix-uterus, and rectum were delineated and volume changes in bladder and rectum filling were calculated. The preand post-fraction CBCT scans were aligned to the bony anatomy to quantify intra-fraction patient setup motion. To quantify intra-fraction displacements of the cervix-uterus, an in-house developed point-based non-rigid registration method was used to nonrigidly align the pre-fraction target shape to the post-fraction one (Fig. 1a). The intra-fraction distances were projected on the average cervix-uterus shape obtained by the non-rigid registration. Finally, intra-fraction cervix-uterus motion was correlated to volume differences in bladder. Results: The mean time between the preand post-fraction CBCT scans was 20.8±3.2 minutes (1SD). Bladder volume increased on average by 62±55 ml over all treatment fractions and rectum volume increased on average 4.6±32.8 ml. Table 1 summarizes the overall mean, systematic and random error for the intra-fraction patient setup motion, and the mean, SD, and 95 percentile for the intra-fraction cervix-uterus motion. Figure 1b shows for one patient a color representation of the treatment-averaged intra-fraction distances projected on the patient’s average cervix-uterus shape. The population-mean intra-fraction cervix-uterus displacements were 3.0±1.4, 4.7±2.8, and 3.4±2.1 mm projected on the LR, CC, and AP axis, respectively. There was a significant correlation between bladder inflow rate and cervix-uterus motion (R=0.6 and p<0.01).