Diaphragm and abdominal organ motion during radiotherapy: a comprehensive multicenter study in 189 children.

BACKGROUND: For accurate thoracic and abdominal radiotherapy, inter- and intrafractional geometrical uncertainties need to be considered to enable accurate margin sizes. We aim to quantify interfractional diaphragm and abdominal organ position variations, and intrafractional diaphragm motion in a large multicenter cohort of pediatric cancer patients (< 18 years). We investigated the correlation of interfractional position variations and intrafractional motion with age, and with general anesthesia (GA). METHODS: In 189 children (mean age 8.1; range 0.4-17.9 years) from six institutes, interfractional position variation of both hemidiaphragms, spleen, liver, left and right kidneys was quantified using a two-step registration. CBCTs were registered to the reference CT relative to the bony anatomy, followed by organ registration. We calculated the group mean, systematic and random errors (standard deviations Σ and σ, respectively) in cranial-caudal (CC), left-right and anterior-posterior directions. Intrafractional right hemidiaphragm motion was quantified using CBCTs on which the breathing amplitude, defined as the difference between end-inspiration and end-expiration peaks, was assessed (N = 79). We investigated correlations with age (Spearman's ρ), and differences in motion between patients treated with and without GA (N = 75; all < 5.5 years). RESULTS: Interfractional group means were largest in CC direction and varied widely between patients, with largest variations in the right hemidiaphragm (range -13.0-17.5 mm). Interfractional group mean of the left kidney showed a borderline significant correlation with age (p = 0.047; ρ = 0.17). Intrafractional right hemidiaphragm motion in patients ≥ 5.5 years (mean 10.3 mm) was significantly larger compared to patients < 5.5 years treated without GA (mean 8.3 mm) (p = 0.02), with smaller Σ and σ values. We found a significant correlation between breathing amplitude and age (p < 0.001; ρ = 0.43). Interfractional right hemidiaphragm position variations were significantly smaller in patients < 5.5 years treated with GA than without GA (p = 0.004), but intrafractional motion showed no significant difference. CONCLUSION: In this large multicenter cohort of children undergoing thoracic and abdominal radiotherapy, we found that interfractional position variation does not depend on age, but the use of GA in patients < 5.5 years showed smaller systematic and random errors. Furthermore, our results showed that breathing amplitude increases with age. Moreover, variations between patients advocate the need for a patient-specific margin approach.

Accuracy of abdominal organ motion estimation in radiotherapy using the right hemidiaphragm top as a surrogate during prolonged breath-holds quantified with MRI.

BACKGROUND: Respiratory motion presents a challenge in radiotherapy of thoracic and upper abdominal tumors. Techniques to account for respiratory motion include tracking. Using magnetic resonance imaging (MRI) guided radiotherapy systems, tumors can be tracked continuously. Using conventional linear accelerators, tracking of lung tumors is possible by determining tumor motion on kilo voltage (kV) imaging. But tracking of abdominal tumors with kV imaging is hampered by limited contrast. Therefore, surrogates for the tumor are used. One of the possible surrogates is the diaphragm. However, there is no universal method for establishing the error when using a surrogate and there are particular challenges in establishing such errors during free breathing (FB). Prolonged breath-holding might address these challenges. PURPOSE: The aim of this study was to quantify the error when using the right hemidiaphragm top (RHT) as surrogate for abdominal organ motion during prolonged breath-holds (PBH) for possible application in radiation treatments. METHODS: Fifteen healthy volunteers were trained to perform PBHs in two subsequent MRI sessions (PBH-MRI1 and PBH-MRI2). From each MRI acquisition, we selected seven images (dynamics) to determine organ displacement during PBH by using deformable image registration (DIR). On the first dynamic, the RHT, right and left hemidiaphragm, liver, spleen and right and left kidney were segmented. We used the deformation vector fields (DVF), generated by DIR, to determine the displacement of each organ between two dynamics in inferior-superior (IS), anterior-posterior (AP), left-right (LR) direction and we calculated the 3D vector magnitude (|d|). The displacements of the RHT, both hemidiaphragms and the abdominal organs were compared using a linear fit to determine the correlation (R2 of the fit) and the displacement ratio (DR, slope of the fit) between displacements of the RHT and each organ. We quantified the median difference between the DRs of PBH-MRI1 and PBH-MRI2 for each organ. Additionally, we estimated organ displacement in the second PBH by applying the DR from the first PBH to the displacement of the RHT measured during the second PBH. We compared the estimated organ displacement to the measured organ displacement during the second PBH. The difference between the two values was defined as the estimation error of using the RHT as a surrogate and assuming a constant DR over MRI sessions. RESULTS: The linear relationships were confirmed by the high R2 values of the linear fit between the displacements of the RHT and the abdominal organs (R2 > 0.96) in the IS and AP direction and |d|, and high to moderate correlations in the LR direction (0.93 > R2 > 0.64). The median DR difference between PBH-MRI1 and PBH-MRI2 varied between 0.13 and 0.31 for all organs. The median estimation error of the RHT as a surrogate varied between 0.4 and 0.8 mm/min for all organs. CONCLUSION: The RHT could serve as an accurate surrogate for abdominal organ motion during radiation treatments, for example, in tracking, provided the error of the RHT as motion surrogate is taken into account in the margins. TRIAL REGISTRATION: The study was registered in the Netherlands Trial Register (NL7603).

Validation and Comparison of Radiograph-Based Organ Dose Reconstruction Approaches for Wilms Tumor Radiation Treatment Plans.

Purpose: Our purpose was to validate and compare the performance of 4 organ dose reconstruction approaches for historical radiation treatment planning based on 2-dimensional radiographs. Methods and Materials: We considered 10 patients with Wilms tumor with planning computed tomography images for whom we developed typical historic Wilms tumor radiation treatment plans, using anteroposterior and posteroanterior parallel-opposed 6 MV flank fields, normalized to 14.4 Gy. Two plans were created for each patient, with and without corner blocking. Regions of interest (lungs, heart, nipples, liver, spleen, contralateral kidney, and spinal cord) were delineated, and dose-volume metrics including organ mean and minimum dose (Dmean and Dmin) were computed as the reference baseline for comparison. Dosimetry for the 20 plans was then independently reconstructed using 4 different approaches. Three approaches involved surrogate anatomy, among which 2 used demographic-matching criteria for phantom selection/building, and 1 used machine learning. The fourth approach was also machine learning-based, but used no surrogate anatomies. Absolute differences in organ dose-volume metrics between the reconstructed and the reference values were calculated. Results: For Dmean and Dmin (average and minimum point dose) all 4 dose reconstruction approaches performed within 10% of the prescribed dose (≤1.4 Gy). The machine learning-based approaches showed a slight advantage for several of the considered regions of interest. For Dmax (maximum point dose), the absolute differences were much higher, that is, exceeding 14% (2 Gy), with the poorest agreement observed for near-beam and out-of-beam organs for all approaches. Conclusions: The studied approaches give comparable dose reconstruction results, and the choice of approach for cohort dosimetry for late effects studies should still be largely driven by the available resources (data, time, expertise, and funding).

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.

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.

Re­irradiation plus hyperthermia for recurrent pediatric sarcoma; a simulation study to investigate feasibility.

Recurrent pediatric tumors pose a challenge since treatment options may be limited, particularly after previous irradiation. Positive results have been reported for chemotherapy and hyperthermia, but the combination of re­irradiation and hyperthermia has not been investigated thus far, although it is a proven treatment strategy in adults. The theoretical feasibility of re­irradiation plus hyperthermia was investigated for infield recurrent pediatric sarcoma in the pelvic region and the extremities. A total of 46 recurrent pediatric sarcoma cases diagnosed at the Academic Medical Center (Amsterdam, The Netherlands) between 2002 and 2017 were evaluated. Patients not previously irradiated, outfield recurrences and locations other than the pelvis and extremities were excluded, ultimately yielding four eligible patients: Two with sarcomas in the pelvis and two in an extremity. Re­irradiation and hyperthermia treatment plans were simulated for 23x2 Gy treatment schedules and weekly hyperthermia. The radiosensitizing effect of hyperthermia was quantified using biological modelling with a temperature­dependent change in the parameters of the linear­quadratic model. The possible effectiveness of re­irradiation plus hyperthermia was estimated by calculating the equivalent radiotherapy dose distribution. Treatment planning revealed that tumors located in the pelvis and the extremities can be effectively heated in children. Equivalent dose distributions indicated that hyperthermic radiosensitization can be quantified as a target­selective additional D95% of typically 10 Gy, thereby delivering a possibly curative dose of 54 Gy, without substantially increasing the equivalent dose to the organs at risk. Therefore, re­irradiation plus hyperthermia is a theoretically feasible and possibly effective treatment option for recurrent pediatric sarcoma in the pelvic region and the extremities, and its clinical feasibility is worthy of evaluation.

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.

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.

Prediction of Ischemic Heart Disease and Stroke in Survivors of Childhood Cancer.

Purpose We aimed to predict individual risk of ischemic heart disease and stroke in 5-year survivors of childhood cancer. Patients and Methods Participants in the Childhood Cancer Survivor Study (CCSS; n = 13,060) were observed through age 50 years for the development of ischemic heart disease and stroke. Siblings (n = 4,023) established the baseline population risk. Piecewise exponential models with backward selection estimated the relationships between potential predictors and each outcome. The St Jude Lifetime Cohort Study (n = 1,842) and the Emma Children's Hospital cohort (n = 1,362) were used to validate the CCSS models. Results Ischemic heart disease and stroke occurred in 265 and 295 CCSS participants, respectively. Risk scores based on a standard prediction model that included sex, chemotherapy, and radiotherapy (cranial, neck, and chest) exposures achieved an area under the curve and concordance statistic of 0.70 and 0.70 for ischemic heart disease and 0.63 and 0.66 for stroke, respectively. Validation cohort area under the curve and concordance statistics ranged from 0.66 to 0.67 for ischemic heart disease and 0.68 to 0.72 for stroke. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups. The cumulative incidences at age 50 years among CCSS low-risk groups were < 5%, compared with approximately 20% for high-risk groups ( P < .001); cumulative incidence was only 1% for siblings ( P < .001 v low-risk survivors). Conclusion Information available to clinicians soon after completion of childhood cancer therapy can predict individual risk for subsequent ischemic heart disease and stroke with reasonable accuracy and discrimination through age 50 years. These models provide a framework on which to base future screening strategies and interventions.

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.

Risk of Symptomatic Stroke After Radiation Therapy for Childhood Cancer: A Long-Term Follow-Up Cohort Analysis.

PURPOSE: Long-term childhood cancer survivors are at high risk of late adverse effects, including stroke. We aimed to determine the cumulative incidence of clinically validated symptomatic stroke (transient ischemic attack [TIA], cerebral infarction, and intracerebral hemorrhage [ICH]) and to quantify dose-effect relationships for cranial radiation therapy (CRT) and supradiaphragmatic radiation therapy (SDRT). METHODS AND MATERIALS: Our single-center study cohort included 1362 survivors of childhood cancer that were diagnosed between 1966 and 1996. Prescribed CRT and SDRT doses were converted into the equivalent dose in 2-Gy fractions (EQD2). Multivariate Cox regression models were used to analyze the relationship between the EQD2 and stroke. RESULTS: After a median latency time of 24.9 years and at a median age of 31.2 years, 28 survivors had experienced a first stroke: TIA (n=5), infarction (n=13), and ICH (n=10). At an attained age of 45 years, the estimated cumulative incidences, with death as competing risk, among survivors treated with CRT only, SDRT only, both CRT and SDRT, and neither CRT nor SDRT were, respectively, 10.0% (95% confidence interval [CI], 2.5%-17.0%), 5.4% (95% CI, 0%-17.0%), 12.5% (95% CI, 5.5%-18.9%), and 0.1% (95% CI, 0%-0.4%). Radiation at both locations significantly increased the risk of stroke in a dose-dependent manner (hazard ratios: HRCRT 1.02 Gy(-1); 95% CI, 1.01-1.03, and HRSDRT 1.04 Gy(-1); 95% CI, 1.02-1.05). CONCLUSIONS: Childhood cancer survivors treated with CRT, SDRT, or both have a high stroke risk. One in 8 survivors treated at both locations will have experienced a symptomatic stroke at an attained age of 45 years. Further research on the pathophysiologic processes involved in stroke in this specific group of patients is needed to enable the development of tailored secondary prevention strategies.

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.

The use of equivalent radiation dose in the evaluation of late effects after childhood cancer treatment.

PURPOSE: In epidemiologic research radiation-associated late effects after childhood cancer are usually analyzed without considering fraction dose. According to radiobiological principles, fraction dose is an important determinant of late effects. We aim to provide the rationale for using equivalent dose in 2-Gy fractions (EQD2(α/ß)) as the measure of choice rather than total physical dose as prescribed according to the clinical protocol. METHODS: Between 1966 and 1996, 597 (43.8%) children in our cohort of 1,362 5-year childhood cancer survivors (CCS) received radiotherapy before the age of 18 years as part of their primary cancer treatment. Detailed information from individual patients' charts was collected and physical doses were converted into the EQD2(α/ß), which includes total dose, fraction dose, and the tissue-specific α/ß ratio. The use of EQD2(α/ß) is illustrated in examples studies describing different analyses using EQD2(α/ß) and physical dose. RESULTS: Radiotherapy information was obtained for 510 (85.4%) CCS. Multivariable analyses rendered different risk estimates for total body irradiation in EQD2(α/ß)-based vs. physical-dose-based models. For other radiotherapy regimens, risk estimates were similar. CONCLUSIONS: Using the total physical dose is not adequate for advanced analyses of radiation-associated late effects in CCS. Therefore, it is advised that for future studies the EQD2(α/ß) is used, because the EQD2(α/ß) incorporates the fraction dose, and the tissue-specific α/ß ratio. Furthermore, it enables comparisons across fractionation regimens and allows for summing doses delivered by various contemporary and future radiation modalities. IMPLICATIONS FOR CANCER SURVIVORS: Risk estimates of radiation-associated side effects expressed in EQD2(α/ß) provide more precise, clinically relevant information for cancer survivor screening guidelines.

Dose-effect relationships for adverse events after cranial radiation therapy in long-term childhood cancer survivors.

PURPOSE: To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships. METHODS AND MATERIALS: The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD(2)). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 years after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD(2) in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy. RESULTS: There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD(2), we found significant dose-effect relationships for these and other AEs. CONCLUSION: Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD(2) instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.

Evaluation of late adverse events in long-term wilms' tumor survivors.

PURPOSE: To evaluate the prevalence and severity of adverse events (AEs) and treatment-related risk factors in long-term Wilms' tumor (WT) survivors, with special attention to radiotherapy. METHODS AND MATERIALS: The single-center study cohort consisted of 185 WT survivors treated between 1966 and 1996, who survived at least 5 years after diagnosis. All survivors were invited to a late-effects clinic for medical assessment of AEs. AEs were graded for severity in a standardized manner. Detailed radiotherapy data enabled us to calculate the equivalent dose in 2 Gy fractions (EQD(2)) to compare radiation doses in a uniform way. Risk factors were evaluated with multivariate logistic regression analysis. RESULTS: Medical follow-up was complete for 98% of survivors (median follow-up, 18.9 years; median attained age, 22.9 years); 123 survivors had 462 AEs, of which 392 had Grade 1 or 2 events. Radiotherapy to flank/abdomen increased the risk of any AE (OR, 1.08 Gy(-1) [CI, 1.04-1.13]). Furthermore, radiotherapy to flank/abdomen was associated with orthopedic events (OR, 1.09 Gy(-1) [CI, 1.05-1.13]) and second tumors (OR, 1.11 Gy(-1) [CI, 1.03-1.19]). Chest irradiation increased the risk of pulmonary events (OR, 1.14 Gy(-1) [CI, 1.06-1.21]). Both flank/abdominal and chest irradiation were associated with cardiovascular events (OR, 1.05 Gy(-1) [CI, 1.00-1.10], OR, 1.06 Gy(-1) [CI, 1.01-1.12]) and tissue hypoplasia (OR, 1.17 Gy(-1) [CI, 1.10-1.24], OR 1.10 Gy(-1) [CI, 1.03-1.18]). CONCLUSION: The majority of AEs, overall as well as in irradiated survivors, were mild to moderate. Nevertheless, the large amount of AEs emphasizes the importance of follow-up programs for WT survivors.