The Pediatric Proton and Photon Therapy Comparison Cohort: Study Design for a Multicenter Retrospective Cohort to Investigate Subsequent Cancers After Pediatric Radiation Therapy.

Purpose: The physical properties of protons lower doses to surrounding normal tissues compared with photons, potentially reducing acute and long-term adverse effects, including subsequent cancers. The magnitude of benefit is uncertain, however, and currently based largely on modeling studies. Despite the paucity of directly comparative data, the number of proton centers and patients are expanding exponentially. Direct studies of the potential risks and benefits are needed in children, who have the highest risk of radiation-related subsequent cancers. The Pediatric Proton and Photon Therapy Comparison Cohort aims to meet this need. Methods and Materials: We are developing a record-linkage cohort of 10,000 proton and 10,000 photon therapy patients treated from 2007 to 2022 in the United States and Canada for pediatric central nervous system tumors, sarcomas, Hodgkin lymphoma, or neuroblastoma, the pediatric tumors most frequently treated with protons. Exposure assessment will be based on state-of-the-art dosimetry facilitated by collection of electronic radiation records for all eligible patients. Subsequent cancers and mortality will be ascertained by linkage to state and provincial cancer registries in the United States and Canada, respectively. The primary analysis will examine subsequent cancer risk after proton therapy compared with photon therapy, adjusting for potential confounders and accounting for competing risks. Results: For the primary aim comparing overall subsequent cancer rates between proton and photon therapy, we estimated that with 10,000 patients in each treatment group there would be 80% power to detect a relative risk of 0.8 assuming a cumulative incidence of subsequent cancers of 2.5% by 15 years after diagnosis. To date, 9 institutions have joined the cohort and initiated data collection; additional centers will be added in the coming year(s). Conclusions: Our findings will affect clinical practice for pediatric patients with cancer by providing the first large-scale systematic comparison of the risk of subsequent cancers from proton compared with photon therapy.

Radiation exposure and leukaemia risk among cohorts of persons exposed to low and moderate doses of external ionising radiation in childhood.

BACKGROUND: Many high-dose groups demonstrate increased leukaemia risks, with risk greatest following childhood exposure; risks at low/moderate doses are less clear. METHODS: We conducted a pooled analysis of the major radiation-associated leukaemias (acute myeloid leukaemia (AML) with/without the inclusion of myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL)) in ten childhood-exposed groups, including Japanese atomic bomb survivors, four therapeutically irradiated and five diagnostically exposed cohorts, a mixture of incidence and mortality data. Relative/absolute risk Poisson regression models were fitted. RESULTS: Of 365 cases/deaths of leukaemias excluding chronic lymphocytic leukaemia, there were 272 AML/CML/ALL among 310,905 persons (7,641,362 person-years), with mean active bone marrow (ABM) dose of 0.11 Gy (range 0-5.95). We estimated significant (P < 0.005) linear excess relative risks/Gy (ERR/Gy) for: AML (n = 140) = 1.48 (95% CI 0.59-2.85), CML (n = 61) = 1.77 (95% CI 0.38-4.50), and ALL (n = 71) = 6.65 (95% CI 2.79-14.83). There is upward curvature in the dose response for ALL and AML over the full dose range, although at lower doses (<0.5 Gy) curvature for ALL is downwards. DISCUSSION: We found increased ERR/Gy for all major types of radiation-associated leukaemia after childhood exposure to ABM doses that were predominantly (for 99%) <1 Gy, and consistent with our prior analysis focusing on <100 mGy.

Fetal and Maternal Atomic Bomb Survivor Dosimetry Using the J45 Pregnant Female Phantom Series: Considerations of the Kneeling and Lying Posture with Comparisons to the DS02 System.

ABSTRACT: Organ dosimetry data of the atomic bomb survivors and the resulting cancer risk models derived from these data are currently assessed within the DS02 dosimetry system developed through the Joint US-Japan Dosimetry Working Group. In DS02, the anatomical survivor models are limited to three hermaphroditic stylized phantoms-an adult (55 kg), a child (19.8 kg), and an infant (9.7 kg)-that were originally designed for the preceding DS86 dosimetry system. As such, organ doses needed for assessment of in-utero cancer risks to the fetus have continued to rely upon the use of the uterine wall in the adult non-pregnant stylized phantom as the dose surrogate for all fetal organs regardless of gestational age. To address these limitations, the Radiation Effects Research Foundation (RERF) Working Group on Organ Dose (WGOD) has established the J45 (Japan 1945) series of high-resolution voxel phantoms, which were derived from the UF/NCI series of hybrid phantoms and scaled to match mid-1940s Japanese body morphometries. The series includes male and female phantoms-newborn to adult-and four pregnant female phantoms at gestational ages of 8, 15, 25, and 38 wk post-conception. In previous studies, we have reported organ dose differences between those reported by the DS02 system and those computed by the WGOD using 3D Monte Carlo radiation transport simulations of atomic bomb gamma-ray and neutron fields for the J45 phantoms series in their traditional "standing" posture, with some variations in their facing direction relative to the bomb hypocenter. In this present study, we present the J45 pregnant female phantoms in both a "kneeling" and "lying" posture and assess the dosimetric impact of these more anatomically realistic survivor models in comparison to current organ doses given by the DS02 system. For the kneeling phantoms facing the bomb hypocenter, organ doses from bomb source photon spectra were shown to be overestimated by the DS02 system by up to a factor of 1.45 for certain fetal organs and up to a factor of 1.17 for maternal organs. For lying phantoms with their feet in the direction of the hypocenter, fetal organ doses from bomb source photon spectra were underestimated by the DS02 system by factors as low as 0.77, while maternal organ doses were overestimated by up to a factor of 1.38. Organs doses from neutron contributions to the radiation fields exhibited an increasing overestimation by the DS02 stylized phantoms as gestational age increased. These discrepancies are most evident in fetal organs that are more posterior within the mother's womb, such as the fetal brain. Further analysis revealed that comparison of these postures to the original standing posture indicate significant dose differences for both maternal and fetal organ doses depending on the type of irradiation. Results from this study highlight the degree to which the existing DS02 system can differ from organ dosimetry based upon 3D radiation transport simulations using more anatomically realistic models of those survivors exposed during pregnancy.

Comparison of out-of-field normal tissue dose estimates for pencil beam scanning proton therapy: MCNP6, PHITS, and TOPAS.

Monte Carlo (MC) methods are considered the gold-standard approach to dose estimation for normal tissues outside the treatment field (out-of-field) in proton therapy. However, the physics of secondary particle production from high-energy protons are uncertain, particularly for secondary neutrons, due to challenges in performing accurate measurements. Instead, various physics models have been developed over the years to reenact these high-energy interactions based on theory. It should thus be acknowledged that MC users must currently accept some unknown uncertainties in out-of-field dose estimates. In the present study, we compared three MC codes (MCNP6, PHITS, and TOPAS) and their available physics models to investigate the variation in out-of-field normal tissue dosimetry for pencil beam scanning proton therapy patients. Total yield and double-differential (energy and angle) production of two major secondary particles, neutrons and gammas, were determined through irradiation of a water phantom at six proton energies (80, 90, 100, 110, 150, and 200 MeV). Out-of-field normal tissue doses were estimated for intracranial irradiations of 1-, 5-, and 15-year-old patients using whole-body computational phantoms. Notably, the total dose estimates for each out-of-field organ varied by approximately 25% across the three codes, independent of its distance from the treatment volume. Dose discrepancies amongst the codes were linked to the utilized physics model, which impacts the characteristics of the secondary radiation field. Using developer-recommended physics, TOPAS produced both the highest neutron and gamma doses to all out-of-field organs from all examined conditions; this was linked to its highest yields of secondary particles and second hardest energy spectra. Subsequent results when using other physics models found reduced yields and energies, resulting in lower dose estimates. Neutron dose estimates were the most impacted by physics model choice, and thus the variation in out-of-field dose estimates may be even larger than 25% when considering biological effectiveness.

Fetal dose from proton pencil beam scanning craniospinal irradiation during pregnancy: a Monte Carlo study.

Objective. We conducted a Monte Carlo study to comprehensively investigate the fetal dose resulting from proton pencil beam scanning (PBS) craniospinal irradiation (CSI) during pregnancy.Approach. The gestational-age dependent pregnant phantom series developed at the University of Florida (UF) were converted into DICOM-RT format (CT images and structures) and imported into a treatment planning system (TPS) (Eclipse v15.6) commissioned to a IBA PBS nozzle. A proton PBS CSI plan (prescribed dose: 36 Gy) was created on the phantoms. The TOPAS MC code was used to simulate the proton PBS CSI on the phantoms, for which MC beam properties at the nozzle exit (spot size, spot divergence, mean energy, and energy spread) were matched to IBA PBS nozzle beam measurement data. We calculated mean absorbed doses for 28 organs and tissues and whole body of the fetus at eight gestational ages (8, 10, 15, 20, 25, 30, 35, and 38 weeks). For contextual purposes, the fetal organ/tissue doses from the treatment planning CT scan of the mother's head and torso were estimated using the National Cancer Institute dosimetry system for CT (NCICT, Version 3) considering a low-dose CT protocol (CTDIvol: 8.97 mGy).Main results. The majority of the fetal organ/tissue doses from the proton PBS CSI treatment fell within a range of 3-6 mGy. The fetal organ/tissue doses for the 38 week phantom showed the largest variation with the doses ranging from 2.9 mGy (adrenals) to 8.2 mGy (eye lenses) while the smallest variation ranging from 3.2 mGy (oesophagus) to 4.4 mGy (brain) was observed for the doses for the 20 week phantom. The fetal whole-body dose ranged from 3.7 mGy (25 weeks) to 5.8 mGy (8 weeks). Most of the fetal doses from the planning CT scan fell within a range of 7-13 mGy, approximately 2-to-9 times lower than the fetal dose equivalents of the proton PBS CSI treatment (assuming a quality factor of 7).Significance. The fetal organ/tissue doses observed in the present work will be useful for one of the first clinically informative predictions on the magnitude of fetal dose during proton PBS CSI during pregnancy.

Body region-specific 3D age-scaling functions for scaling whole-body computed tomography anatomy for pediatric late effects studies.

Purpose.Radiation epidemiology studies of childhood cancer survivors treated in the pre-computed tomography (CT) era reconstruct the patients' treatment fields on computational phantoms. For such studies, the phantoms are commonly scaled to age at the time of radiotherapy treatment because age is the generally available anthropometric parameter. Several reference size phantoms are used in such studies, but reference size phantoms are only available at discrete ages (e.g.: newborn, 1, 5, 10, 15, and Adult). When such phantoms are used for RT dose reconstructions, the nearest discrete-aged phantom is selected to represent a survivor of a specific age. In this work, we (1) conducted a feasibility study to scale reference size phantoms at discrete ages to various other ages, and (2) evaluated the dosimetric impact of using exact age-scaled phantoms as opposed to nearest age-matched phantoms at discrete ages.Methods.We have adopted the University of Florida/National Cancer Institute (UF/NCI) computational phantom library for our studies. For the feasibility study, eight male and female reference size UF/NCI phantoms (5, 10, 15, and 35 years) were downscaled to fourteen different ages which included next nearest available lower discrete ages (1, 5, 10 and 15 years) and the median ages at the time of RT for Wilms' tumor (3.9 years), craniospinal (8.0 years), and all survivors (9.1 years old) in the Childhood Cancer Survivor Study (CCSS) expansion cohort treated with RT. The downscaling was performed using our in-house age scaling functions (ASFs). To geometrically validate the scaling, Dice similarity coefficient (DSC), mean distance to agreement (MDA), and Euclidean distance (ED) were calculated between the scaled and ground-truth discrete-aged phantom (unscaled UF/NCI) for whole-body, brain, heart, liver, pancreas, and kidneys. Additionally, heights of the scaled phantoms were compared with ground-truth phantoms' height, and the Centers for Disease Control and Prevention (CDC) reported 50th percentile height. Scaled organ masses were compared with ground-truth organ masses. For the dosimetric assessment, one reference size phantom and seventeen body-size dependent 5-year-old phantoms (9 male and 8 female) of varying body mass indices (BMI) were downscaled to 3.9-year-old dimensions for two different radiation dose studies. For the first study, we simulated a 6 MV photon right-sided flank field RT plan on a reference size 5-year-old and 3.9-year-old (both of healthy BMI), keeping the field size the same in both cases. Percent of volume receiving dose ≥15 Gy (V15) and the mean dose were calculated for the pancreas, liver, and stomach. For the second study, the same treatment plan, but with patient anatomy-dependent field sizes, was simulated on seventeen body-size dependent 5- and 3.9-year-old phantoms with varying BMIs. V15, mean dose, and minimum dose received by 1% of the volume (D1), and by 95% of the volume (D95) were calculated for pancreas, liver, stomach, left kidney (contralateral), right kidney, right and left colons, gallbladder, thoracic vertebrae, and lumbar vertebrae. A non-parametric Wilcoxon rank-sum test was performed to determine if the dose to organs of exact age-scaled and nearest age-matched phantoms were significantly different (p < 0.05).Results.In the feasibility study, the best DSCs were obtained for the brain (median: 0.86) and whole-body (median: 0.91) while kidneys (median: 0.58) and pancreas (median: 0.32) showed poorer agreement. In the case of MDA and ED, whole-body, brain, and kidneys showed tighter distribution and lower median values as compared to other organs. For height comparison, the overall agreement was within 2.8% (3.9 cm) and 3.0% (3.2 cm) of ground-truth UF/NCI and CDC reported 50th percentile heights, respectively. For mass comparison, the maximum percent and absolute differences between the scaled and ground-truth organ masses were within 31.3% (29.8 g) and 211.8 g (16.4%), respectively (across all ages). In the first dosimetric study, absolute difference up to 6% and 1.3 Gy was found for V15and mean dose, respectively. In the second dosimetric study, V15and mean dose were significantly different (p < 0.05) for all studied organs except the fully in-beam organs. D1and D95were not significantly different for most organs (p > 0.05).Conclusion.We have successfully evaluated our ASFs by scaling UF/NCI computational phantoms from one age to another age, which demonstrates the feasibility of scaling any CT-based anatomy. We have found that dose to organs of exact age-scaled and nearest aged-matched phantoms are significantly different (p < 0.05) which indicates that using the exact age-scaled phantoms for retrospective dosimetric studies is a better approach.

Lymphoma and multiple myeloma in cohorts of persons exposed to ionising radiation at a young age.

There is limited evidence that non-leukaemic lymphoid malignancies are radiogenic. As radiation-related cancer risks are generally higher after childhood exposure, we analysed pooled lymphoid neoplasm data in nine cohorts first exposed to external radiation aged <21 years using active bone marrow (ABM) and, where available, lymphoid system doses, and harmonised outcome classification. Relative and absolute risk models were fitted. Years of entry spanned 1916-1981. At the end of follow-up (mean 42.1 years) there were 593 lymphoma (422 non-Hodgkin (NHL), 107 Hodgkin (HL), 64 uncertain subtype), 66 chronic lymphocytic leukaemia (CLL) and 122 multiple myeloma (MM) deaths and incident cases among 143,136 persons, with mean ABM dose 0.14 Gy (range 0-5.95 Gy) and mean age at first exposure 6.93 years. Excess relative risk (ERR) was not significantly increased for lymphoma (ERR/Gy = -0.001; 95% CI: -0.255, 0.279), HL (ERR/Gy = -0.113; 95% CI: -0.669, 0.709), NHL + CLL (ERR/Gy = 0.099; 95% CI: -0.149, 0.433), NHL (ERR/Gy = 0.068; 95% CI: -0.253, 0.421), CLL (ERR/Gy = 0.320; 95% CI: -0.678, 1.712), or MM (ERR/Gy = 0.149; 95% CI: -0.513, 1.063) (all p-trend > 0.4). In six cohorts with estimates of lymphatic tissue dose, borderline significant increased risks (p-trend = 0.02-0.07) were observed for NHL + CLL, NHL, and CLL. Further pooled epidemiological studies are needed with longer follow-up, central outcome review by expert hematopathologists, and assessment of radiation doses to lymphoid tissues.

Stylized versus voxel phantoms: a juxtaposition of organ depth distributions.

For external irradiation, the variability in organ dose estimation found between computational phantom generations arises particularly from the differences in organ positioning. This work represents the first effort to quantify the differences in organ depth below the body surface between a stylized and voxel phantom series. Herein, the revised Oak Ridge National Laboratory stylized phantom series and the University of Florida/National Cancer Institute voxel phantom series were compared. Both series include whole-body models of the newborn; the 1-, 5-, 10-, and 15-year-old; and the adult human. Organ depths from eight different directions applicable to external irradiation geometries were computed: antero-posterior, postero-anterior, left and right lateral, rotational, isotropic, cranial and caudal directions. Organ depths in the stylized phantoms were computed using a ray-tracing technique available through Monte Carlo radiation transport simulations in MCNP6. Organ depths in the voxel phantom were found using phantom matrix manipulation. Resultant organ depths for both series were plotted as distributions; available are twenty-four organs and two bone tissue distributions for each of six phantom ages and in each of the eight directional geometries. Quantitative data descriptors (e.g. mean and median depths) were also tabulated. For demonstration purposes, a literature review of relevant stylized versus voxel comparison works was performed to explore where the quantification of organ depth differences can provide further insight or evidence to study conclusions. The entire dataset of organ depth distributions and their data descriptors can be found in online supplementary files.

Conversion of computational human phantoms into DICOM-RT for normal tissue dose assessment in radiotherapy patients.

Radiotherapy (RT) treatment planning systems (TPS) are designed for the fast calculation of dose to the tumor bed and nearby organs at risk using x-ray computed tomography (CT) images. However, CT images for a patient are typically available for only a small portion of the body, and in some cases, such as for retrospective epidemiological studies, no images may be available at all. When dose to organs that lie out-of-scan must be estimated, a convenient alternative for the unknown patient anatomy is to use a matching whole-body computational phantom as a surrogate. The purpose of the current work is to connect such computational phantoms to commercial RT TPS for retrospective organ dose estimation. A custom software with graphical user interface (GUI), called the DICOM-RT Generator, was developed in MATLAB to convert voxel computational phantoms into the digital imaging and communications in medicine radiotherapy (DICOM-RT) format, compatible with commercial TPS. DICOM CT image sets for the phantoms are created via a density-to-Hounsfield unit (HU) conversion curve. Accompanying structure sets containing the organ contours are automatically generated by tracing binary masks of user-specified organs on each phantom CT slice. The software was tested on a library of body size-dependent phantoms, the International Commission on Radiological Protection reference phantoms, and a canine voxel phantom, taking only a few minutes per conversion. The resulting DICOM-RT files were tested on several commercial TPS. As an example application, a library of converted phantoms was used to estimate organ doses for members of the National Wilms Tumor Study (NWTS) cohort. The converted phantom library, in DICOM format, and a standalone MATLAB-compiled executable of the DICOM-RT Generator are available for others to use for research purposes (http://ncidose.cancer.gov).