Nine years of plan of the day for cervical cancer: Plan library remains effective compared to fully online-adaptive techniques.

BACKGROUND AND PURPOSE: Since 2011, our center has been using a library-based Plan-of-the-Day (PotD) strategy for external beam radiotherapy of cervical cancer patients to reduce normal tissue dose while maintaining adequate target coverage. With the advent of fully online-adaptive techniques such as daily online-adaptive replanning, further dose reduction may be possible. However, it is unknown how this reduction relates to plan library approaches, and how the most recent PotD strategies relate to no adaptation. In this study we compare the performance of our current PotD strategy with non-adaptive and fully online-adaptive techniques in terms of target volume size and normal tissue sparing. MATERIALS AND METHODS: Treatment data of 376 patients treated with the PotD protocol between June 2011 and April 2020 were included. The size of the Planning Target Volumes (PTVs) was reconstructed for different strategies: full online adaptation, no adaptation, and the latest clinical version of the PotD protocol. Normal tissue sparing was estimated by the difference in margin volume to construct the PTV and the volume overlap of the PTV with bladder and rectum. RESULTS: The current version of our PotD approach reduced the PTV margin volume by a median of 250 cm3 compared to no adaptation. Bladder-PTV overlap decreased from a median of 142 to 71 cm3, and from 39 to 16 cm3 for rectum-PTV. Fully online-adaptive approaches could further decrease the PTV volume by 144 cm3 using a 5 mm margin for residual errors. In this scenario, bladder-PTV overlap was reduced to 35 cm3 and rectum-PTV overlap to 11 cm3. CONCLUSION: The current version of the PotD protocol is an effective technique to improve normal tissue sparing compared to no adaptation. Further sparing can be achieved using fully online-adaptive techniques, but at the cost of a more complex workflow and with a potentially limited impact. PotD-type protocols can therefore be considered as a suitable alternative to fully online-adaptive approaches.

Improving organs-at-risk sparing for choroidal melanoma patients: A CT-based two-beam strategy in ocular proton therapy with a dedicated eyeline.

PURPOSE: To investigate the potential clinical benefit of a two-beam arrangement technique using three-dimensional (3D) imaging of uveal melanoma (UM) patients treated with proton therapy and a dedicated eyeline. MATERIAL/METHODS: Retrospective CT-based treatment plans of 39 UM patients performed using a single beam (SB) were compared to plans with two beams (TB) optimized for better trade-offs in organs-at-risk sparing. The RBE-weighted prescribed dose was 60 Gy (DRBE, GTV = 60 Gy) in four fractions, assuming an RBE of 1.1. Dosimetric findings were analyzed for three patient groups based on tumor-optic nerve distance and UM staging (group GrA: ≤3 mm, T1 T2 UM; GrB: ≤3 mm, T3 UM; GrC: >3 mm, T1 T2 T3 UM). Finally, two schedules were compared on biologically effective dose (BED): both beams being delivered either the same day (TB), or on alternate days (TBalter). RESULTS: All strategies resulted in dosimetrically acceptable plans. A dose reduction to the anterior structures was achieved in 23/39 cases with the two-beam plans. D25% was significantly lowered compared to SB plans by 12.4 and 15.4 Gy RBE-weighted median dose in GrA and GrB, respectively. D2% was reduced by 18.6 and 6.0 Gy RBE-weighted median dose in GrA and GrB, respectively. A cost to the optic nerve was observed with a median difference up to 3.8 Gy RBE-weighted dose in GrB. BED differences were statistically significant for all considered parameters in favor of two beams delivered the same day. CONCLUSION: A two-beam strategy appears beneficial for posterior tumors abutting the optic nerve. This strategy might have a positive impact on the risk of ocular complications.

Impact of interfractional target motion in locally advanced cervical cancer patients treated with spot scanning proton therapy using an internal target volume strategy.

BACKGROUND AND PURPOSE: The more localized dose deposition of proton therapy (PT) compared to photon therapy might allow a reduction in treatment-related side effects but induces additional challenges to address. The aim of this study was to evaluate the impact of interfractional motion on the target and organs at risk (OARs) in cervical cancer patients treated with spot scanning PT using an internal target volume (ITV) strategy. METHODS AND MATERIALS: For ten locally advanced cervical cancer patients, empty and full bladder planning computed tomography (pCT) as well as 25 daily cone beam CTs (CBCTs) were available. The Clinical Target Volume (CTV), the High Risk CTV (CTVHR) (gross tumor volume and whole cervix), the non-involved uterus as well as the OARs (bowel, bladder and rectum) were contoured on the daily CBCTs and transferred to the pCT through rigid bony match. Using synthetic CTs derived from pCTs, four-beam spot scanning PT plans were generated to target the patient-specific ITV with 45 Gy(RBE) in 25 fractions. This structure was defined based on pre-treatment MRI and CT to anticipate potential target motion throughout the treatment. D98% of the targets and V40Gy(RBE) of the OARs were extracted from the daily anatomies, accumulated and analyzed. In addition, the impact of bladder volume deviations from planning values on target and bowel dose was investigated. RESULTS: The ITV strategy ensured a total accumulated dose >42.75 Gy(RBE) to the CTVHR for all ten patients. Two patients with large bladder-related uterus motion had accumulated dose to the non-involved uterus of 35.7 Gy(RBE) and 41.1 Gy(RBE). Variations in bowel V40Gy(RBE) were found to be correlated (Pearson r = -0.55; p-value <0.0001) with changes in bladder volume during treatment. CONCLUSION: The ITV concept ensured adequate dose to the CTVHR, but was insufficient for the non-involved uterus of patients subject to large target interfractional motion. CBCT monitoring and occasional replanning is recommended along the same lines as with photon radiotherapy in cervical cancer.

Dosimetric Impact of Intrafraction Motion in Online-Adaptive Intensity Modulated Proton Therapy for Cervical Cancer.

PURPOSE: A method was recently developed for online-adaptive intensity modulated proton therapy (IMPT) in patients with cervical cancer. The advantage of this approach, relying on the use of tight margins, is challenged by the intrafraction target motion. The purpose of this study was to evaluate the dosimetric effect of intrafraction motion on the target owing to changes in bladder filling in patients with cervical cancer treated with online-adaptive IMPT. METHODS AND MATERIALS: In 10 patients selected to have large uterus motion induced by bladder filling, the intrafraction anatomic changes were simulated for several prefraction durations for online (automated) contouring and planning. For each scenario, the coverage of the primary target was evaluated with margins of 2.5 and 5 mm. RESULTS: Using a 5- mm planning target volume margin, median accumulated D98% was greater than 42.75 GyRBE1.1 (95% of the prescribed dose) in the case of a prefraction duration of 5 and 10 minutes. For a prefraction duration of 15 minutes, this parameter deteriorated to 42.6 GyRBE1.1. When margins were reduced to 2.5 mm, only a 5-minute duration resulted in median target D98% above 42.75 GyRBE1.1. In addition, smaller bladders were found to be associated with larger dose degradations compared with larger bladders. CONCLUSIONS: This study indicates that intrafraction anatomic changes can have a substantial dosimetric effect on target coverage in an online-adaptive IMPT scenario for patients subject to large uterus motion. A margin of 5 mm was sufficient to compensate for the intrafraction motion due to bladder filling for up to 10 minutes of prefraction time. However, compensation for the uncertainties that were disregarded in this study, by using margins or robust optimization, is also required. Furthermore, a large bladder volume restrains intrafraction target motion and is recommended for treating patients in this scenario. Assuming that online-adaptive IMPT remains beneficial as long as narrow margins are used (5 mm or below), this study demonstrates its feasibility with regard to intrafraction motion.

A model-based patient selection tool to identify who may be at risk of exceeding dose tolerances during pancreatic SBRT.

PURPOSE: Locally advanced pancreatic cancer (LAPC) patients are prone to experience daily anatomical variations, which can lead to additional doses in organs-at-risk (OAR) during SBRT. A patient selection tool was developed to identify who may be at risk of exceeding dose tolerances, by quantifying the dosimetric impact of daily variations using an OAR motion model. MATERIALS AND METHODS: The study included 133 CT scans from 35 LAPC patients. By following a leave-one-out approach, an OAR motion model trained with the remaining 34 subjects variations was used to simulate organ deformations on the left-out patient planning CT anatomy. Dose-volume histograms obtained from planned doses sampled on simulated organs resulted in the probability of exceeding OAR dose-constraints due to anatomical variations. Simulated probabilities were clustered with a threshold per organ according to clinical observations. If the prediction of at least one OAR was above the established thresholds, the patient was classified as being at risk. RESULTS: Clinically, in 20/35 patients at least one OAR exceeded dose-constraints in the daily CTs. The model-based prediction had an accuracy of 89%, 71%, 91% in estimating the risk of exceeding dose tolerances for the duodenum, stomach and bowel, respectively. By combining the three predictions, our approach resulted in a correct patient classification for 29/35 patients (83%) when compared with clinical observations. CONCLUSIONS: Our model-based patient selection tool is able to predict who might be at risk of exceeding dose-constraints during SBRT. It is a promising tool to tailor LAPC treatments, e.g. by employing online adaptive SBRT; and hence, to minimize toxicity of patients being at risk.

Modeling daily changes in organ-at-risk anatomy in a cohort of pancreatic cancer patients.

PURPOSE: To characterize daily geometrical variations of gastrointestinal organs with respect to pancreatic tumors, through a population-based statistical model. MATERIALS AND METHODS: The study included 131 CT scans from 35 pancreatic cancer patients treated with Stereotactic Body Radiotherapy (SBRT). For each patient, day-to-day anatomical variations of the stomach, the duodenum and the bowel were assessed from the deformation vector fields (DVF) obtained by non-rigidly registering the contours of the fractions to the planning CT scans. For the whole population, day-to-day motion-deformation patterns were abstracted using principal component analysis (PCA) on the set of DVFs mapped on a reference patient. Based on these geometrical variations, anatomies were generated to create population-based dose-volume histograms (DVH) per patient, which were also compared to clinical values. RESULTS: Through PCA, the most dominant directions of daily deformations were localized in the abdominal organs. Common patterns were found, such as stomach contraction-expansion in the anterior-posterior direction ranging from 5 to 13 mm, and superior-inferior deformations on the bowel from 7 to 14 mm. The duodenum resulted to move laterally, but in a lesser extent (4-8 mm). The population-based DVHs derived from the model mostly included the daily DVHs observed in the clinic (in >90% of the cases). CONCLUSIONS: Anatomical variations influence the delivered doses to healthy organs during SBRT. A motion model was successfully built and explored to extract the larger directions of movement of the gastrointestinal organs. Day-to-day motion modeling can potentially be used to account for geometrical uncertainties in future plan optimization and in online adaptive strategies.

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

BACKGROUND AND PURPOSE: Planned 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. MATERIALS AND METHOD: Prescribed dose-escalation to the prostate was 67.5 Gy/25fr., corresponding to 81GyEQD2 assuming α/ß = 1.5. The 21 patients had three targets (i.e. CTV67.5 + 2 mm, CTV60 + 5 mm, CTV50 + 10 mm) 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. RESULTS: Discrepancies 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 (n = 8) and without (n = 13) recurrence (p > 0.05). Average D98%/EUD with statistical dose-accumulation vs DVH-summation was significantly different in CTV60, CTV50, rectum and bladder but not in CTV67.5. CONCLUSION: The 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.

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

BACKGROUND AND PURPOSE: With 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. MATERIALS AND METHODS: A 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. RESULTS: The 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. CONCLUSION: Intra-fraction cervix-uterus motion can be considerable and should be taken into account using appropriate PTV margins.

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

PURPOSE: In 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. METHODS: T2w-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). RESULTS: The 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. CONCLUSIONS: The 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.

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

BACKGROUND AND PURPOSE: Deformation 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). MATERIAL AND METHODS: The 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. RESULTS: The 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. CONCLUSIONS: Treatment 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.

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

UNLABELLED: 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.

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 PURPOSE: To predict the lowest achievable rectum D35 for quality assurance of IMRT plans of prostate cancer patients. MATERIALS AND METHODS: For 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. RESULTS: After 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. CONCLUSIONS: For 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.

PURPOSE: Computer 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. METHODS: Contrast-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. RESULTS: Liver 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). CONCLUSIONS: An 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.