Comparative assessment and QA measurement array validation of Monte Carlo and Collapsed Cone dose algorithms for small fields and clinical treatment plans.

PURPOSE: Many studies have demonstrated superior performance of Monte Carlo (MC) over type B algorithms in heterogeneous structures. However, even in homogeneous media, MC dose simulations should outperform type B algorithms in situations of electronic disequilibrium, such as small and highly modulated fields. Our study compares MC and Collapsed Cone (CC) dose algorithms in RayStation 12A. Under consideration are 6 MV and 6 MV flattening filter-free (FFF) photon beams, relevant for VMAT plans such as head-and-neck and stereotactic lung treatments with heterogeneities, as well as plans for multiple brain metastases in one isocenter, involving highly modulated small fields. We aim to investigate collimator angle dependence of small fields and performance differences between different combinations of ArcCHECK configuration and dose algorithm. METHODS: Several verification tests were performed, ranging from simple rectangular fields to highly modulated clinical plans. To evaluate and compare the performance of the models, the agreements between calculation and measurement are compared between MC and CC. Measurements include water tank measurements for test fields, ArcCHECK measurements for test fields and VMAT plans, and film dosimetry for small fields. RESULTS AND CONCLUSIONS: In very small or narrow fields, our measurements reveal a strong dependency of dose output to collimator angle for VersaHD with Agility MLC, reproduced by both dose algorithms. ArcCHECK results highlight a suboptimal agreement between measurements and MC calculations for simple rectangular fields when using inhomogeneous ArcCHECK images. Therefore, we advocate for the use of homogeneous phantom images, particularly for static fields, in ArcCHECK verification with MC. MC might offer performance benefits for more modulated treatment fields. In ArcCHECK results for clinical plans, MC performed comparable to CC for 6 MV. For 6 MV FFF and the preferred homogeneous phantom image, MC resulted in consistently better results (13%-64% lower mean gamma index) compared to CC.

Pediatric radiotherapy for thoracic and abdominal targets: Organ motion, reported margin sizes, and delineation variations - A systematic review.

For radiotherapy of thoracic and abdominal tumors safety margins are applied to address geometrical uncertainties caused by e.g. set-up errors, organ motion and delineation variability. For pediatric patients no standardized margins are defined. Moreover, studies on these geometrical uncertainties are relatively scarce. Therefore, this systematic review presents an overview of organ motion, applied margin sizes and delineation variability in patients <18 years. A search from January 2000 to March 2021 in Medline, Embase, Web of Science, ClinicalTrials.gov and the International Trials Registry Platform resulted in the inclusion of 117 studies reporting on organ motion, margin sizes and/or delineation variability. Studies were heterogeneous concerning age, tumor types, the use of general anesthesia, imaging modalities; image guidance techniques were reported in 39% of the studies. Inter- and intrafractional motion as reported for different organs was largest in cranio-caudal direction and ranged from -9.1 to 10.0 mm and -4.4 to 19.5 mm, respectively. Motion quantification methodologies differed between studies regarding measures of displacement and definitions of motion direction. Reported CTV-PTV margins varied from 3 to 20 mm for both thoracic and abdominal targets, and for spinal and pelvic from 3to 15 mm and 3 to 10 mm, respectively. Studies reported wide variation in interobserver variability of target volume delineation, which may affect dose distributions to both target volumes and organs at risk. Results of this review indicate possible reduction of margin sizes for children, however, wide variation in organ motion and delineation variability caused by differences in methodologies and outcomes hamper the use of standardized margins.

Dosimetric feasibility of hypofractionation for metastatic bone/bone marrow lesions from paediatric solid tumours.

BACKGROUND AND PURPOSE: The aim of this study was to determine the feasibility of hypofractionated schedules for metastatic bone/bone marrow lesions in children and to investigate dosimetric differences to the healthy surrounding tissues compared to conventional schedules. METHODS: 27 paediatric patients (mean age, 7 years) with 50 metastatic bone/bone marrow lesions (n = 26 cranial, n = 24 extra-cranial) from solid primary tumours (neuroblastoma and sarcoma) were included. The PTV was a 2 mm expansion of the GTV. A prescription dose of 36 and 54 Gy EQD2α/ß=10 was used for neuroblastoma and sarcoma lesions, respectively. VMAT plans were optimized for each single lesion using different fractionation schedules: conventional (30/20 fractions, V95% ≥ 99%, D0.1cm3 ≤ 107%) and hypofractionated (15/10/5/3 fractions, V100% ≥ 95%, D0.1cm3 ≤ 120%). Relative EQD2 differences in OARs Dmean between the different schedules were compared. RESULTS: PTV coverage was met for all plans independently of the fractionation schedule and for all lesions (V95% range 95.5-100%, V100% range 95.1-100%), with exception of the vertebrae (V100% range 63.5-91.0%). For most OARs, relative mean reduction in the Dmean was seen for the hypofractionated plans compared to the conventional plans, with largest sparing in the 5 fractions (< 43%) followed by the 3 fractions schedule (< 40%). In case of PTV overlap with an OAR, a significant increase in dose for the OAR was observed with hypofractionation. CONCLUSIONS: For the majority of the cases, iso-effective plans with hypofractionation were feasible with similar or less dose in the OARs. The most suitable fractionation schedule should be personalised depending on the spatial relationship between the PTV and OARs and the prescription dose.

Radical radiotherapy for paediatric solid tumour metastases: An overview of current European protocols and outcomes of a SIOPE multicenter survey.

PURPOSE/OBJECTIVE: About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries. MATERIALS/METHODS: Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating ≥50 children annually were invited to participate in an online survey. RESULTS: Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied. CONCLUSION: Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST.

The effectiveness of 4DCT in children and adults: A pooled analysis.

BACKGROUND: While four-dimensional computed tomography (4DCT) is extensively used in adults, reluctance remains to use 4DCT in children. Day-to-day (interfractional) variability and irregular respiration (intrafractional variability) have shown to be limiting factors of 4DCT effectiveness in adults. In order to evaluate 4DCT applicability in children, the purpose of this study is to quantify inter- and intrafractional variability of respiratory motion in children and adults. The pooled analysis enables a solid comparison to reveal if 4DCT application for planning purposes in children could be valid. METHODS/MATERIALS: We retrospectively included 90 patients (45 children and 45 adults), for whom the diaphragm was visible on abdominal/thoracic free-breathing cone beam CTs (480 pediatric, 524 adult CBCTs). For each CBCT, the cranial-caudal position of end-exhale and end-inhale positions of the right diaphragm dome were manually selected in the projection images. The difference in position between both phases defines the amplitude. Cycle time equaled inspiratory plus expiratory time. We analyzed the variability of the inter- and intrafractional respiratory-induced diaphragm motion. RESULTS: Ranges of respiratory motion characteristics were large in both children and adults (amplitude: 4-17 vs 5-24 mm, cycle time 2.1-3.9 vs 2.7-6.5 s). The mean amplitude was slightly smaller in children than in adults (10.7 vs 12.3 mm; P = 0.06). Interfractional amplitude variability was statistically significantly smaller in children than in adults (1.4 vs 2.2 mm; P = 0.00). Mean cycle time was statistically significantly shorter in children (2.9 vs 3.6 s; P = 0.00). Additionally, intrafractional cycle time variability was statistically significantly smaller in children (0.5 vs 0.7 s; P = 0.00). CONCLUSIONS: Overall variability is smaller in children than in adults, indicating that respiratory motion is more regular in children than in adults. This implies that a single pretreatment 4DCT could be a good representation of daily respiratory motion in children and will be at least equally beneficial for planning purposes as it is in adults.

Predictive value of pediatric respiratory-induced diaphragm motion quantified using pre-treatment 4DCT and CBCTs.

BACKGROUND: In adults, a single pre-treatment four-dimensional CT (4D-CT) acquisition is often used to account for respiratory-induced target motion during radiotherapy. However, studies have indicated that a 4D-CT is not always representative for respiratory motion. Our aim was to investigate whether respiratory-induced diaphragm motion in children on a single pre-treatment 4DCT can accurately predict respiratory-induced diaphragm motion as observed on cone beam CTs (CBCTs). METHODS: Twelve patients (mean age 14.5 yrs.; range 8.6-17.9 yrs) were retrospectively included based on visibility of the diaphragm on abdominal or thoracic imaging data acquired during free breathing. A 4DCT for planning purposes and daily/weekly CBCTs (total 125; range 4-29 per patient) acquired prior to dose delivery were available. The amplitude, corresponding to the difference in position of the diaphragm in cranial-caudal direction in end-inspiration and end-expiration phases, was extracted from the 4DCT (A4DCT). The amplitude in CBCTs (ACBCT) was defined as displacement between averaged in- and expiration diaphragm positions on corresponding projection images, and the distribution of ACBCT was compared to A4DCT (one-sample t-test, significance level p < 0.05). RESULTS: Over all patients, the mean A4DCT was 10.4 mm and the mean ACBCT 11.6 mm. For 9/12 patients, A4DCT differed significantly (p < 0.05) from ACBCT. Differences > 3 mm were found in 69/125 CBCTs (55%), with A4DCT mostly underestimating ACBCT. For 7/12 patients, diaphragm positions differed significantly from the baseline position. CONCLUSION: Respiratory-induced diaphragm motion determined on 4DCT does not accurately predict the daily respiratory-induced diaphragm motion observed on CBCTs, as the amplitude and baseline position differed statistically significantly in the majority of patients. Regular monitoring of respiratory motion during the treatment course using CBCTs could yield a higher accuracy when a daily adaptation to the actual breathing amplitude takes place.

Abdominal organ position variation in children during image-guided radiotherapy.

BACKGROUND: Interfractional organ position variation might differ for abdominal organs and this could have consequences for defining safety margins. Therefore, the purpose of this study is to quantify interfractional position variations of abdominal organs in children in order to investigate possible correlations between abdominal organs and determine whether position variation is location-dependent. METHODS: For 20 children (2.2-17.8 years), we retrospectively analyzed 113 CBCTs acquired during the treatment course, which were registered to the reference CT to assess interfractional position variation of the liver, spleen, kidneys, and both diaphragm domes. Organ position variation was assessed in three orthogonal directions and relative to the bony anatomy. Diaphragm dome position variation was assessed in the cranial-caudal (CC) direction only. We investigated possible correlations between position variations of the organs (Spearman's correlation test, ρ), and tested if organ position variations in the CC direction are related to the diaphragm dome position variations (linear regression analysis, R2) (both tests: significance level p < 0.05). Differences of variations of systematic (∑) and random errors (σ) between organs were tested (Bonferroni significance level p < 0.004). RESULTS: In all directions, correlations between liver and spleen position variations, and between right and left kidney position variations were weak (ρ ≤ 0.43). In the CC direction, the position variations of the right and left diaphragm domes were significantly, and stronger, correlated with position variations of the liver (R2 = 0.55) and spleen (R2 = 0.63), respectively, compared to the right (R2 = 0.00) and left kidney (R2 = 0.25). Differences in ∑ and σ between all organs were small and insignificant. CONCLUSIONS: No (strong) correlations between interfractional position variations of abdominal organs in children were observed. From present results, we concluded that diaphragm dome position variations could be more representative for superiorly located abdominal (liver, spleen) organ position variations than for inferiorly located (kidneys) organ position variations. Differences of systematic and random errors between abdominal organs were small, suggesting that for margin definitions, there was insufficient evidence of a dependence of organ position variation on anatomical location.

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.

Global loss of myelin water over 5 years in multiple sclerosis normal-appearing white matter.

BACKGROUND: Reduced myelin water fraction (MWF, a marker for myelin), increased geometric mean T2 (ieGMT2, reflecting intra/extracellular water properties), and increased T1 (related to total water content) have been observed in cross-sectional studies of multiple sclerosis (MS) normal-appearing white matter (NAWM). OBJECTIVE: To assess longitudinal changes of magnetic resonance (MR) measures in relapsing-remitting MS (RRMS) brain NAWM. METHODS: A total of 11 subjects with RRMS and 4 controls were scanned on a 3T MRI at baseline and long-term follow-up (LTFU; 3.2-5.8 years) with a 32-echo T2 relaxation and an inversion recovery T1 sequence. For every voxel, MWF, ieGMT2, and T1 were obtained. Mean, peak height, and peak location from NAWM mask-based histograms were determined. RESULTS: In MS subjects, NAWM MWF mean decreased by 8% ( p = 0.0016). No longitudinal changes were measured in T1 or ieGMT2. There was no relationship between change in any MR metric and change in EDSS. Control white matter showed no differences over time in any metric. CONCLUSION: The decreases we observed in MWF suggest that changes in myelin integrity and loss of myelin may be occurring diffusely and over long time periods in the MS brain. The timescale of these changes indicates that chronic, progressive myelin damage is an evolving process occurring over many years.

Magnitude and variability of respiratory-induced diaphragm motion in children during image-guided radiotherapy.

BACKGROUND AND PURPOSE: To analyse the variability of respiratory motion during image-guided radiotherapy in paediatric cancer patients and to investigate possible relationships thereof with patient-specific factors. MATERIAL AND METHODS: Respiratory-induced diaphragm motion was retrospectively analysed on 480 cone beam CTs acquired during the treatment course of 45 children (<18years). The cranial-caudal positions of the top of the right diaphragm in exhale and inhale phases were manually selected in the projection images. The difference in position between both phases defines the amplitude. The cycle time equalled inspiratory plus expiratory time. We analysed the variability of the intra- and interfractional respiratory motion and studied possible correlations between respiratory-induced diaphragm motion and age, height, and weight. RESULTS: Over all patients, mean amplitude and cycle time were 10.7mm (range 4.1-17.4mm) and 2.9s (range 2.1-3.9s). Intrafractional variability was larger than interfractional variability (2.4mmvs. 1.4mm and 0.5svs. 0.4s for amplitude and cycle time, respectively). Correlations between mean amplitude and patient-specific factors were significant but weak (p<0.05, ρ≤0.45). CONCLUSIONS: Large ranges of amplitude and cycle time and weak correlations confirm that respiratory motion is patient-specific and requires an individualized approach to account for. Since interfractional variability was small, we suggest that a pre-treatment 4DCT in children could be sufficiently predictive to quantify the respiratory motion.

Interfractional renal and diaphragmatic position variation during radiotherapy in children and adults: is there a difference?

BACKGROUND: Pediatric safety margins are generally based on data from adult studies; however, adult-based margins might be too large for children. The aim of this study was to quantify and compare interfractional organ position variation in children and adults. MATERIAL AND METHODS: For 35 children and 35 adults treated with thoracic/abdominal irradiation, 850 (range 5-30 per patient) retrospectively collected cone beam CT images were registered to the reference CT that was used for radiation treatment planning purposes. Renal position variation was assessed in three orthogonal directions and summarized as 3D vector lengths. Diaphragmatic position variation was assessed in the cranio-caudal (CC) direction only. We calculated means and SDs to estimate group systematic (Σ) and random errors (σ) of organ position variation. Finally, we investigated possible correlations between organ position variation and patients' height. RESULTS: Interfractional organ position variation was different in children and adults. Median 3D right and left kidney vector lengths were significantly smaller in children than in adults (2.8, 2.9 mm vs. 5.6, 5.2 mm, respectively; p < .05). Generally, the pediatric Σ and σ were significantly smaller than in adults (p < .007). Overall and within both subgroups, organ position variation and patients' height were only negligibly correlated. CONCLUSIONS: Interfractional renal and diaphragmatic position variation in children is smaller than in adults indicating that pediatric margins should be defined differently from adult margins. Underlying mechanisms and other components of geometrical uncertainties need further investigation to explain differences and to appropriately define pediatric safety margins.

Quantification of renal and diaphragmatic interfractional motion in pediatric image-guided radiation therapy: A multicenter study.

BACKGROUND AND PURPOSE: To quantify renal and diaphragmatic interfractional motion in order to estimate systematic and random errors, and to investigate the correlation between interfractional motion and patient-specific factors. MATERIAL AND METHODS: We used 527 retrospective abdominal-thoracic cone beam CT scans of 39 childhood cancer patients (<18 years) to quantify renal motion relative to bony anatomy in the left-right (LR), cranio-caudal (CC) and anterior-posterior (AP) directions, and diaphragmatic motion in the CC direction only. Interfractional motion was quantified by distributions of systematic and random errors in each direction (standard deviations Σ and σ, respectively). Also, correlation between organ motion and height was analyzed. RESULTS: Inter-patient organ motion varied widely, with the largest movements in the CC direction. Values of Σ in LR, CC, and AP directions were 1.1, 3.8, 2.1 mm for the right, and 1.3, 3.0, 1.5 mm for the left kidney, respectively. The σ in these three directions was 1.1, 3.1, 1.7 mm for the right, and 1.2, 2.9, 2.1 mm for the left kidney, respectively. For the diaphragm we estimated Σ=5.2 mm and σ=4.0 mm. No correlations were found between organ motion and height. CONCLUSIONS: The large inter-patient organ motion variations and the lack of correlation between motion and patient-related factors, suggest that individualized margin approaches might be required.