Online adaptive radiotherapy for bladder cancer using a simultaneous integrated boost and fiducial markers.

PURPOSE: The aim was to assess the feasibility of online adaptive radiotherapy (oART) for bladder cancer using a focal boost by focusing on the quality of the online treatment plan and automatic target delineation, duration of the workflow and performance in the presence of fiducial markers for tumor bed localization. METHODS: Fifteen patients with muscle invasive bladder cancer received daily oART with Cone Beam CT (CBCT), artificial intelligence (AI)-assisted automatic delineation of the daily anatomy and online plan reoptimization. The bladder and pelvic lymph nodes received a total dose of 40 Gy in 20 fractions, the tumor received an additional simultaneously integrated boost (SIB) of 15 Gy. The dose distribution of the reference plan was calculated for the daily anatomy, i.e. the scheduled plan. Simultaneously, a reoptimization of the plan was performed i.e. the adaptive plan. The target coverage and V95% outside the target were evaluated for both plans. The need for manual adjustments of the GTV delineation, the duration of the workflow and the influence of fiducial markers were assessed. RESULTS: All 300 adaptive plans met the requirement of the CTV-coverage V95%≥98% for both the boost (55 Gy) and elective volume (40 Gy). For the scheduled plans the CTV-coverage was 53.5% and 98.5%, respectively. Significantly less tissue outside the targets received 55 Gy in case of the adaptive plans as compared to the scheduled plans. Manual corrections of the GTV were performed in 67% of the sessions. In 96% of these corrections the GTV was enlarged and resulted in a median improvement of 1% for the target coverage. The median on-couch time was 22 min. A third of the session time consisted of reoptimization of the treatment plan. Fiducial markers were visible on the CBCTs and aided the tumor localization. CONCLUSIONS: AI-driven CBCT-guided oART aided by fiducial markers is feasible for bladder cancer radiotherapy treatment including a SIB. The quality of the adaptive plans met the clinical requirements and fiducial markers were visible enabling consistent daily tumor localization. Improved automatic delineation to lower the need for manual corrections and faster reoptimization would result in shorter session time.

Automatic landmark correspondence detection in medical images with an application to deformable image registration.

Purpose: Deformable image registration (DIR) can benefit from additional guidance using corresponding landmarks in the images. However, the benefits thereof are largely understudied, especially due to the lack of automatic landmark detection methods for three-dimensional (3D) medical images. Approach: We present a deep convolutional neural network (DCNN), called DCNN-Match, that learns to predict landmark correspondences in 3D images in a self-supervised manner. We trained DCNN-Match on pairs of computed tomography (CT) scans containing simulated deformations. We explored five variants of DCNN-Match that use different loss functions and assessed their effect on the spatial density of predicted landmarks and the associated matching errors. We also tested DCNN-Match variants in combination with the open-source registration software Elastix to assess the impact of predicted landmarks in providing additional guidance to DIR. Results: We tested our approach on lower abdominal CT scans from cervical cancer patients: 121 pairs containing simulated deformations and 11 pairs demonstrating clinical deformations. The results showed significant improvement in DIR performance when landmark correspondences predicted by DCNN-Match were used in the case of simulated ( p = 0 e 0 ) as well as clinical deformations ( p = 0.030 ). We also observed that the spatial density of the automatic landmarks with respect to the underlying deformation affect the extent of improvement in DIR. Finally, DCNN-Match was found to generalize to magnetic resonance imaging scans without requiring retraining, indicating easy applicability to other datasets. Conclusions: DCNN-match learns to predict landmark correspondences in 3D medical images in a self-supervised manner, which can improve DIR performance.

Characterization of Ethos therapy systems for adaptive radiation therapy: A multi-machine comparison.

PURPOSE: The recently released Ethos therapy system (Varian Medical Systems) allows for online CBCT-guided adaptive radiation therapy (RT). The clinical introduction of multiple systems requires machine characterization and machine variation quantification to allow patient interchangeability between systems. Despite several clinical introductions, limited vendor-independent information on machine performance is available. Our aim was to determine the relevant dosimetric and mechanical characteristics of individual machines and to quantify machine variations. METHODS: Six Ethos treatment machines, equipped with a 6-MV FFF beam including dual-layer MLC and kV-CBCT system, were recently introduced clinically after extensive machine characterization and pre-configured beam model verification. Point doses and profiles were measured and compared to vendor-provided reference data and dose calculations. Also, dose calculations were verified based on point measurements for non-standard fields and dose distributions for optimized treatment plans. Agreements between dose profiles (dose distributions) were quantified using 1D (3D) γ-analysis. Additionally, we quantified leaf transmission, dosimetric leaf gap (DLG) and couch attenuation, determined isocenter accuracy and kV-MV isocenter coincidence and verified the kV-CBCT system. Machine variations were quantified for all dosimetric and mechanical characteristics. RESULTS: For all machines, distinct agreements were found between measurements and vendor-provided reference data as well as measurements and dose calculations. Mean γ1%/1mm values for all profiles were below 0.30. All profiles, point measurements and dose distributions matched well among the six machines. Minimal machine variations were found in terms of DLG (0.05 mm), leaf transmission (0.001%), isocenter accuracy (0.08 mm), kV-MV isocenter coincidence (0.15 mm), couch attenuation (0.69%), and CBCT imaging dose (0.29 mGy). CONCLUSIONS: This study demonstrates excellent agreement between individual Ethos therapy systems and vendor-provided reference data as well as a pre-configured beam model. Furthermore, our results show good consistency among all machines and provide valuable insights on relevant machine characteristics. The systematically obtained results provide benchmark data for future clinical introduction of Ethos therapy systems.

Patterns of Hearing Loss in Irradiated Survivors of Head and Neck Rhabdomyosarcoma.

PURPOSE: The frequency and patterns of HL in a HNRMS survivor cohort were investigated. A dose-effect relationship between the dose to the cochlea and HL was explored. METHODS: Dutch survivors treated for HNRMS between 1993 and 2017 with no relapse and at least two years after the end of treatment were eligible for inclusion. The survivors were evaluated for HL with pure-tone audiometry. HL was graded according to the Muenster, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and International Society for Paediatric Oncology (SIOP) classification. We defined deleterious HL as Muenster ≥ 2b, CTCAE ≥ 2, and SIOP ≥ 2. Mixed-effects logistic regression was used to search for the dose-effect relationship between the irradiation dose to the cochlea and the occurrence of HL. RESULTS: Forty-two HNRMS survivors underwent pure-tone audiometry. The Muenster, CTCAE and SIOP classification showed that 19.0% (n = 8), 14.2% (n = 6) and 11.9% (n = 5) of survivors suffered from HL, respectively. A low-frequency HL pattern with normal hearing or milder hearing loss in the higher frequencies was seen in four survivors. The maximum cochlear irradiation dose was significantly associated with HL (≥Muenster 2b) (p = 0.047). In our series, HL (≥Muenster 2b) was especially observed when the maximum dose to the cochlea exceeded 19 Gy. CONCLUSION: HL occurred in up to 19% of survivors of HNRMS. More research is needed on HL patterns in HNRMS survivors and on radiotherapy dose-effect relationships.

Feasibility of Conebeam CT-based online adaptive radiotherapy for neoadjuvant treatment of rectal cancer.

BACKGROUND: Online adaptive radiotherapy has the potential to reduce toxicity for patients treated for rectal cancer because smaller planning target volumes (PTV) margins around the entire clinical target volume (CTV) are required. The aim of this study is to describe the first clinical experience of a Conebeam CT (CBCT)-based online adaptive workflow for rectal cancer, evaluating timing of different steps in the workflow, plan quality, target coverage and patient compliance. METHODS: Twelve consecutive patients eligible for 5 × 5 Gy pre-operative radiotherapy were treated on a ring-based linear accelerator with a multidisciplinary team present at the treatment machine for each fraction. The accelerator is operated using an integrated software platform for both treatment planning and delivery. In all directions for all CTVs a PTV margin of 5 mm was used, except for the cranial/caudal borders of the total CTV where a margin of 8 mm was applied. A reference plan was generated based on a single planning CT. After aligning the patient the online adaptive procedure started with acquisition of a CBCT. The planning CT scan was registered to the CBCT using deformable registration and a synthetic CT scan was generated. With the support of artificial intelligence, structure guided deformation and the synthetic CT scan contours were adapted by the system to match the anatomy on the CBCT. If necessary, these contours were adjusted before a new plan was generated. A second and third CBCT were acquired to validate the new plan with respect to CTV coverage just before and after treatment delivery, respectively. Treatment was delivered using volumetric modulated arc treatment (VMAT). All steps in this process were defined and timed. RESULTS: On average the timeslot needed at the treatment machine was 34 min. The process of acquiring a CBCT, evaluating and adjusting the contours, creating the new plan and verifying the CTV on the CBCT scan took on average 20 min. Including delivery and post treatment verification this was 26 min. Manual adjustments of the target volumes were necessary in 50% of fractions. Plan quality, target coverage and patient compliance were excellent. CONCLUSIONS: First clinical experience with CBCT-based online adaptive radiotherapy shows it is feasible for rectal cancer. Trial registration Medical Research Involving Human Subjects Act (WMO) does not apply to this study and was retrospectively approved by the Medical Ethics review Committee of the Academic Medical Center (W21_087 # 21.097; Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands).

How do patient characteristics and anatomical features correlate to accuracy of organ dose reconstruction for Wilms' tumor radiation treatment plans when using a surrogate patient's CT scan?

In retrospective radiation treatment (RT) dosimetry, a surrogate anatomy is often used for patients without 3D CT. To gain insight in what the crucial aspects in a surrogate anatomy are to enable accurate dose reconstruction, we investigated the relation of patient characteristics and internal anatomical features with deviations in reconstructed organ dose using surrogate patient's CT scans. Abdominal CT scans of 35 childhood cancer patients (age: 2.1-5.6 yr; 17 boys, 18 girls) undergoing RT during 2004-2016 were included. Based on whether an intact right or left kidney is present in the CT scan, two groups were formed each containing 24 patients. From each group, four CTs associated with Wilms' tumor RT plans with an anterior-posterior-posterior-anterior field setup were selected as references. For each reference, a 2D digitally reconstructed radiograph was computed from the reference CT to simulate a 2D radiographic image and dose reconstruction was performed on the other CTs in the respective group. Deviations in organ mean dose (DEmean) of the reconstructions versus the references were calculated, as were deviations in patient characteristics (i.e. age, height, weight) and in anatomical features including organ volume, location (in 3D), and spatial overlaps. Per reference, the Pearson's correlation coefficient between deviations in DEmean and patient characteristics/features were studied. Deviation in organ locations and DEmean for the liver, spleen, and right kidney were moderately correlated (R2 > 0.5) for 8/8, 5/8, and 3/4 reference plans, respectively. Deviations in organ volume or spatial overlap and DEmean for the right and left kidney were weakly correlated (0.3 < R2 < 0.5) in 4/4 and 1/4 reference plans. No correlations (R2 < 0.3) were found between deviations in age or height and DEmean. Therefore, the performance of organ dose reconstruction using surrogate patients' CT scans is primarily related to deviation in organ location, followed by volume and spatial overlap. Further, results were plan dependent.

Concurrent Daily Cisplatin and High-Dose Radiation Therapy in Patients With Stage III Non-Small Cell Lung Cancer.

PURPOSE: The purpose of this study was to determine survival, local and distant control, toxicity, and prognostic factors in patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiation therapy (CCRT). METHODS AND MATERIALS: Consecutive patients with stage IIIA and IIIB NSCLC (N = 154) staged with 18F-fluorodeoxyglucose positron emission tomography/computed tomography were retrospectively selected (2005-2015). CCRT consisted of daily low-dose cisplatin (6 mg/m2) combined with 24 fractions of 2.75 Gy to a total dose of 66 Gy. RESULTS: During a median follow-up period of 22 months (range, 1-92 months) the median overall survival was 36 months. The 1-, 2-, 3-, and 5-year survival rates were 79% (95% confidence interval [CI], 73%-86%), 61% (95% CI, 54%-70%), 52% (95% CI, 43%-60%), and 40% (95% CI, 31%-51%), respectively. The local relapse-free survival at 5 years was 55% (95% CI, 44%-69%). Metastasis-free survival at 5 years was 53% (95% CI, 44%-65%). The incidence of severe gastrointestinal disorders (grade 3-5) was 11%, among which grade 3 radiation esophagitis was 8.4%. The incidence of severe respiratory, thoracic, and mediastinal disorders (grade 3-5) was 8.4%, among which grade 3 radiation pneumonitis was 1.3%. Predictors of overall survival were lymph node gross tumor volume (GTV) (hazard ratio [HR], 1.007; 95% CI, 1.000-1.012) and sex (HR, 0.500; 95% CI, 0.320-0.870) in favor of women. Although lymph node GTV was a predictor of treatment toxicity (HR, 1.010; 95% CI, 1.000-1.013), tumor GTV was the predictor for distant metastasis during follow-up (HR, 1.002; 95% CI, 1.001-1.003). CONCLUSIONS: CCRT with daily low-dose cisplatin for locally advanced stage III NSCLC resulted in promising overall survival (3-year survival rate of 52% and 5-year survival rate of 40%) with low toxicity. Lymph node GTV, tumor GTV, and sex were predictors of overall survival, treatment toxicity, and distant metastasis.

Heart volume reduction during radiotherapy involving the thoracic region in children: An unexplained phenomenon.

BACKGROUND AND PURPOSE: Radiotherapy involving the thoracic region is associated with cardiotoxicity in long-term childhood cancer survivors. We quantified heart volume changes during radiotherapy in children (<18 years) and investigated correlations with patient and treatment related characteristics. MATERIAL AND METHODS: Between 2010 and 2016, 34 children received radiotherapy involving the thoracic region. We delineated heart contours and measured heart volumes on 114 CBCTs. Relative volume changes were quantified with respect to the volume on the first CBCT (i.e., 100%). Cardiac radiation dose parameters expressed as 2 Gy/fraction equivalent doses were calculated from DVHs. Chemotherapy was categorized as treatment with anthracyclines, alkylating agents, vinca-alkaloids, and other. RESULTS: The overall median heart volume reduction from the first to the last CBCT was 5.5% (interquartile range1.6-9.7%; p < 0.001). Heart volumes decreased significantly between the baseline measurement and the first week (Bonferroni's adjusted p = 0.002); volume changes were not significant during the following weeks. Univariate analysis showed a significant correlation between heart volume reduction and alkylating agents; however, no multivariate analyses could be done to further confirm this. CONCLUSIONS: We found a significant heart volume reduction in children during radiotherapy. Elucidation of underlying mechanisms, clinical relevance, and possible long-term consequences of early heart volume reduction require a prospective follow-up study.

Are age and gender suitable matching criteria in organ dose reconstruction using surrogate childhood cancer patients' CT scans?

PURPOSE: The purpose of this work was to assess the feasibility of using surrogate CT scans of matched patients for organ dose reconstructions for childhood cancer (CC) survivors, treated in the past with only 2D imaging data available instead of 3D CT data, and in particular using the current literature standard of matching patients based on similarity in age and gender. METHODS: Thirty-one recently treated CC patients with abdominal CT scans were divided into six age- and gender-matched groups. From each group, two radiotherapy plans for Wilms' tumor were selected as reference plans and applied to the age- and gender-matched patients' CTs in the respective group. Two reconstruction strategies were investigated: S1) without field adjustments; S2) with manual field adjustments according to anatomical information, using a visual check in digitally reconstructed radiographs. To assess the level of agreement between the reconstructed and the reference dose distributions, we computed (using a collapsed cone algorithm) and compared the absolute deviation in mean and maximum dose normalized by the prescribed dose (i.e., normalized errors |NEmean | and |NE2cc |) in eight organs at risk (OARs): heart, lungs, liver, spleen, kidneys, and spinal cord. Furthermore, we assessed the quality of a reconstruction case by varying acceptance thresholds for |NEmean | and |NE2cc |. A reconstruction case was accepted (i.e., considered to pass) if the errors in all OARs are smaller than the threshold. The pass fraction for a given threshold was then defined as the percentage of reconstruction cases that were classified as a pass. Furthermore, we consider the impact of allowing to use a different CT scan for each OAR. RESULTS: Slightly smaller reconstruction errors were achieved with S2 in multiple OARs than with S1 (P < 0.05). Among OARs, the best reconstruction was found for the spinal cord (average |NEmean | and |NE2cc | ≤ 4%). The largest average |NEmean | was found in the spleen (18%). The largest average |NE2cc | was found in the left lung (26%). Less than 30% of the reconstruction cases (i.e., pass fraction) meet the criteria that |NEmean | < 20% and |NE2cc | < 20% in all OARs when using age and gender matching and a single CT to do reconstructions. Allowing other matchings and combining reconstructions for OARs from multiple patients, the pass fraction increases substantially to more than 60%. CONCLUSIONS: To conclude, reconstructions with small deviations can be obtained by using CC patients' CT scans, making the general approach promising. However, using age and gender as the only matching criteria to select a CT scan for the reconstruction is not sufficient to guarantee sufficiently low reconstruction errors. It is therefore suggested to include more features (e.g., height, features extracted from 2D radiographs) than only age and gender for dose reconstruction for CC survivors treated in the pre-3D radiotherapy planning era and to consider ways to combine multiple reconstructions focused on different OARs.

On the feasibility of automatically selecting similar patients in highly individualized radiotherapy dose reconstruction for historic data of pediatric cancer survivors.

PURPOSE: The aim of this study is to establish the first step toward a novel and highly individualized three-dimensional (3D) dose distribution reconstruction method, based on CT scans and organ delineations of recently treated patients. Specifically, the feasibility of automatically selecting the CT scan of a recently treated childhood cancer patient who is similar to a given historically treated child who suffered from Wilms' tumor is assessed. METHODS: A cohort of 37 recently treated children between 2- and 6-yr old are considered. Five potential notions of ground-truth similarity are proposed, each focusing on different anatomical aspects. These notions are automatically computed from CT scans of the abdomen and 3D organ delineations (liver, spleen, spinal cord, external body contour). The first is based on deformable image registration, the second on the Dice similarity coefficient, the third on the Hausdorff distance, the fourth on pairwise organ distances, and the last is computed by means of the overlap volume histogram. The relationship between typically available features of historically treated patients and the proposed ground-truth notions of similarity is studied by adopting state-of-the-art machine learning techniques, including random forest. Also, the feasibility of automatically selecting the most similar patient is assessed by comparing ground-truth rankings of similarity with predicted rankings. RESULTS: Similarities (mainly) based on the external abdomen shape and on the pairwise organ distances are highly correlated (Pearson rp ≥ 0.70) and are successfully modeled with random forests based on historically recorded features (pseudo-R2 ≥ 0.69). In contrast, similarities based on the shape of internal organs cannot be modeled. For the similarities that random forest can reliably model, an estimation of feature relevance indicates that abdominal diameters and weight are the most important. Experiments on automatically selecting similar patients lead to coarse, yet quite robust results: the most similar patient is retrieved only 22% of the times, however, the error in worst-case scenarios is limited, with the fourth most similar patient being retrieved. CONCLUSIONS: Results demonstrate that automatically selecting similar patients is feasible when focusing on the shape of the external abdomen and on the position of internal organs. Moreover, whereas the common practice in phantom-based dose reconstruction is to select a representative phantom using age, height, and weight as discriminant factors for any treatment scenario, our analysis on abdominal tumor treatment for children shows that the most relevant features are weight and the anterior-posterior and left-right abdominal diameters.

Plan selection strategy for rectum cancer patients: An interobserver study to assess clinical feasibility.

BACKGROUND AND PURPOSE: In radiotherapy for rectum cancer, the target volume is highly deformable. An adaptive plan selection strategy can mitigate the effect of these variations. The purpose of this study was to evaluate the feasibility of an adaptive strategy by assessing the interobserver variation in CBCT-based plan selection. MATERIAL AND METHODS: Eleven patients with rectum cancer, treated with a non-adaptive strategy, were selected. Five CBCT scans were available per patient. To simulate the plan selection strategy, per patient three PTVs were created by varying the anterior upper mesorectum margin. For each CBCT scan, twenty observers selected the smallest PTV that encompassed the target volume. After this initial baseline measurement, the gold standard was determined during a consensus meeting, followed by a second measurement one month later. Differences between both measurements were assessed using the Wilcoxon signed-rank test. RESULTS: In the baseline measurement, the concordance with the gold standard was 69% (range: 60-82%), which improved to 75% (range: 60-87%) in the second measurement (p=0.01). For the second measurement, 10% of plan selections were smaller than the gold standard. CONCLUSION: With a plan selection consistency between observers of 75%, a plan selection strategy for rectum cancer patients is feasible.

Aggressive behaviour of inpatients with acquired brain injury.

OBJECTIVE: To study the prevalence, nature and determinants of aggression among inpatients with acquired brain injury. BACKGROUND: Patients with acquired brain injury often have difficulty in controlling their aggressive impulses. DESIGN: A prospective observational study design. METHODS: By means of the Staff Observation Aggression Scale-Revised, the prevalence, nature and severity of aggressive behaviour of inpatients with acquired brain injury was assessed on a neuropsychiatric treatment ward with 45 beds. Additional data on patient-related variables were gathered from the patients' files. RESULTS: In total, 388 aggressive incidents were recorded over 17 weeks. Of a total of 57 patients included, 24 (42%) patients had engaged in aggressive behaviour on one or more occasions. A relatively small proportion of patients (n=8; 14%) was found to be responsible for the majority of incidents (n=332; 86%). The vast majority of aggression incidents (n=270; 70%) were directly preceded by interactions between patients and nursing staff. In line with this, most incidents occurred at times of high contact intensity. Aggressive behaviour was associated with male gender, length of stay at the ward, legal status and hypoxia as the cause of brain injury. CONCLUSION: Aggression was found to be highly prevalent among inpatients with acquired brain injury. The results suggest that for the prevention of aggression on the ward, it may be highly effective to develop individually tailored interventions for the subgroup with serious aggression problems. RELEVANCE TO CLINICAL PRACTICE: Insight into the frequency, nature and determinants of aggressive behaviour in inpatients with acquired brain injury provides nurses with tools for the prevention and treatment of aggressive behaviour.

Characteristics and performance evaluation of the capacitive Contact Flexible Microstrip Applicator operating at 70 MHz for external hyperthermia.

PURPOSE: To characterise and evaluate the capacitive Contact Flexible Microstrip Applicator operating at 70 MHz, CFMA-70. This applicator is introduced for the treatment of superficial tumours with extension in depth beyond the range of regular superficial applicators. METHODS: E-field measurements were performed in an elliptical phantom filled with a saline solution using an E-field vector probe. E-field distributions and SAR patterns are compared to those of the CFMA-434 and of 70 MHz waveguides. The applicator has been used for the treatment of 6 patients with breast cancer with a tumour depth exceeding 4 cm. RESULTS: The effective heating depth of the CFMA-70 is 50% larger than for the CFMA-434. Its effective field size is 26 x 20 cm (aperture 29 x 20 cm), larger than for an equally sized CFMA-434. In contrast to the CFMA-434 the SAR pattern of this applicator is insensitive to the bolus thickness. Comparison to 70 MHz waveguides shows that the E-field component normal to the applicator is 100% larger for the CFMA-70. During clinical applications acceptable temperatures were realised for individual sessions (also at depth), but in many cases treatment limiting hot spots occurred close to superficial bony structures near the applicator edge. Both surface irregularities and the normal field component may be responsible. CONCLUSIONS: The CFMA-70 has adequate penetration depth for the treatment of superficial tumours exceeding a depth of 4 cm. However, the relatively large normal E-field component may induce treatment-limiting hot spots at tissue interfaces in the direction normal to the applicator's surface.