Risk of Cerebrovascular Events Among Childhood and Adolescent Patients Receiving Cranial Radiation Therapy: A Pediatric Normal Tissue Effects in the Clinic Normal Tissue Outcomes Comprehensive Review.

PURPOSE: Radiation-induced cerebrovascular toxicity is a well-documented sequelae that can be both life-altering and potentially fatal. We performed a meta-analysis of the relevant literature to create practical models for predicting the risk of cerebral vasculopathy after cranial irradiation. METHODS AND MATERIALS: A literature search was performed for studies reporting pediatric radiation therapy (RT) associated cerebral vasculopathy. When available, we used individual patient RT doses delivered to the Circle of Willis (CW) or optic chiasm (as a surrogate), as reported or digitized from original publications, to formulate a dose-response. A logistic fit and a Normal Tissue Complication Probability (NTCP) model was developed to predict future risk of cerebrovascular toxicity and stroke, respectively. This NTCP risk was assessed as a function of prescribed dose. RESULTS: The search identified 766 abstracts, 5 of which were used for modeling. We identified 101 of 3989 pediatric patients who experienced at least one cerebrovascular toxicity: transient ischemic attack, stroke, moyamoya, or arteriopathy. For a range of shorter follow-ups, as specified in the original publications (approximate attained ages of 17 years), our logistic fit model predicted the incidence of any cerebrovascular toxicity as a function of dose to the CW, or surrogate structure: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy. At an attained age of 35 years, our NTCP model predicted a stroke incidence of 0.9% to 1.3%, 1.8% to 2.7%, and 2.8% to 4.1%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.2%-0.3%). At an attained age of 45 years, the predicted incidence of stroke was 2.1% to 4.2%, 4.5% to 8.6%, and 6.7% to 13.0%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.5%-1.0%). CONCLUSIONS: Risk of cerebrovascular toxicity continues to increase with longer follow-up. NTCP stroke predictions are very sensitive to model variables (baseline stroke risk and proportional stroke hazard), both of which found in the literature may be systematically erring on minimization of true risk. We hope this information will assist practitioners in counseling, screening, surveilling, and facilitating risk reduction of RT-related cerebrovascular late effects in this highly sensitive population.

The Advantage of Proton Therapy in Hypothalamic-Pituitary Axis and Hippocampus Avoidance for Children with Medulloblastoma.

PURPOSE: Craniospinal irradiation (CSI) improves clinical outcomes at the cost of long-term neuroendocrine and cognitive sequelae. The purpose of this pilot study was to determine whether hypothalamic-pituitary axis (HPA) and hippocampus avoidance (HPA-HA) with intensity-modulated proton therapy (IMPT) can potentially reduce this morbidity compared with standard x-ray CSI. MATERIALS AND METHODS: We retrospectively evaluated 10 patients with medulloblastoma (mean, 7 years; range, 4-14 years). Target volumes and organs at risk were delineated as per our local protocol and the ACNS0331 atlas. An experienced neuroradiologist verified the HPA and hippocampus contours. The primary objective was CSI and boost clinical target volume (CTV) covering 95% of the volume (D95) > 99% coverage with robustness. Described proton therapy doses in grays are prescribed using a biological effectiveness relative to photon therapy of 1.1. The combined prescribed dose in the boost target was 54 Gy. Secondary objectives included the HPA and hippocampus composite average dose (Dmean ≤ 18 Gy). For each patient, volumetric modulated arc radiotherapy (VMAT) and tomotherapy (TOMO) plans existed previously, and a new plan was generated with 3 cranial and 1 or 2 spinal beams for pencil-beam scanning delivery. Statistical comparison was performed with 1-way analysis of variance. RESULTS: Compared with standard CSI, HPA-HA CSI had statistically significant decreases in the composite doses received by the HPA (32.2 versus 17.9 Gy; P < .001) and hippocampi (39.8 versus 22.8 Gy; P < .001). The composite HPA Dmean was lower in IMPT plans (17.9 Gy) compared with that of VMAT (21.8 Gy) and TOMO (21.2 Gy) plans (P = .05). Hippocampi composite Dmean was also lower in IMPT plans (21 Gy) compared with that of VMAT (27.5 Gy) and TOMO (27.2 Gy) plans (P = .02). The IMPT CTV D95 coverage was lower in IMPT plans (52.8 Gy) compared with that of VMAT (54.6 Gy) and TOMO (54.6 Gy) plans (P < .001) The spared mean volume was only 1.35% (19.8 cm3) of the whole-brain CTV volume (1476 cm3). CONCLUSION: We found that IMPT has the strong potential to reduce the dose to the HPA and hippocampus, compared with standard x-ray CSI while maintaining target coverage. A prospective clinical trial is required to establish the safety, efficacy, and toxicity of this novel CSI approach.

Personalized 3D-printed anthropomorphic whole-body phantom irradiated by protons, photons, and neutrons.

The objective of this study was to confirm the feasibility of three-dimensionally-printed (3D-printed), personalized whole-body anthropomorphic phantoms for radiation dose measurements in a variety of charged and uncharged particle radiation fields. We 3D-printed a personalized whole-body phantom of an adult female with a height of 154.8 cm, mass of 90.7 kg, and body mass index of 37.8 kg/m2. The phantom comprised of a hollow plastic shell filled with water and included a watertight access conduit for positioning dosimeters. It is compatible with a wide variety of radiation dosimeters, including ionization chambers that are suitable for uncharged and charged particles. Its mass was 6.8 kg empty and 98 kg when filled with water. Watertightness and mechanical robustness were confirmed after multiple experiments and transportations between institutions. The phantom was irradiated to the cranium with therapeutic beams of 170-MeV protons, 6-MV photons, and fast neutrons. Radiation absorbed dose was measured from the cranium to the pelvis along the longitudinal central axis of the phantom. The dose measurements were made using established dosimetry protocols and well-characterized instruments. For the therapeutic environments considered in this study, stray radiation from intracranial treatment beams was the lowest for proton therapy, intermediate for photon therapy, and highest for neutron therapy. An illustrative example set of measurements at the location of the thyroid for a square field of 5.3 cm per side resulted in 0.09, 0.59, and 1.93 cGy/Gy from proton, photon, and neutron beams, respectively. In this study, we found that 3D-printed personalized phantoms are feasible, inherently reproducible, and well-suited for therapeutic radiation measurements. The measurement methodologies we developed enabled the direct comparison of radiation exposures from neutron, proton, and photon beam irradiations.

Proton Radiotherapy Could Reduce the Risk of Fatal Second Cancers for Children with Intracranial Tumors in Low- and Middle-Income Countries.

PURPOSE: To test our hypothesis that, for young children with intracranial tumors, proton radiotherapy in a high-income country does not reduce the risk of a fatal subsequent malignant neoplasm (SMN) compared with photon radiotherapy in low- and middle-income countries. MATERIALS AND METHODS: We retrospectively selected 9 pediatric patients with low-grade brain tumors who were treated with 3-dimensional conformal radiation therapy in low- and middle-income countries. Images and contours were deidentified and transferred to a high-income country proton therapy center. Clinically commissioned treatment planning systems of each academic hospital were used to calculate absorbed dose from the therapeutic fields. After fusing supplemental computational phantoms to the patients' anatomies, models from the literature were applied to calculate stray radiation doses. Equivalent doses were determined in organs and tissues at risk of SMNs, and the lifetime attributable risk of SMN mortality (LAR) was predicted using a dose-effect model. Our hypothesis test was based on the average of the ratios of LARs from proton therapy to that of photon therapy ()(H0: = 1; H A : < 1). RESULTS: Proton therapy reduced the equivalent dose in organs at risk for SMNs and LARs compared with photon therapy for which the for the cohort was 0.69 ± 0.10, resulting in the rejection of H0 (P < .001, α = 0.05). We observed that the younger children in the cohort (2-4 years old) were at a factor of approximately 2.5 higher LAR compared with the older children (8-12 years old). CONCLUSION: Our findings suggest that proton radiotherapy has the strong potential of reducing the risk of fatal SMNs in pediatric patients with intracranial tumors if it were made available globally.

ANALYTICAL MODEL TO ESTIMATE EQUIVALENT DOSE FROM INTERNAL NEUTRONS IN PROTON THERAPY OF CHILDREN WITH INTRACRANIAL TUMORS.

This study developed a computationally efficient and easy-to-implement analytical model to estimate the equivalent dose from secondary neutrons originating in the bodies ('internal neutrons') of children receiving intracranial proton radiotherapy. A two-term double-Gaussian mathematical model was fit to previously published internal neutron equivalent dose per therapeutic absorbed dose versus distance from the field edge calculated using Monte Carlo simulations. The model was trained using three intracranial proton fields of a 9-year-old girl. The resulting model was tested against two intracranial fields of a 10-year-old boy by comparing the mean doses in organs at risk of a radiogenic cancer estimated by the model versus those previously calculated by Monte Carlo. On average, the model reproduced the internal neutron organ doses in the 10-year-old boy within 13.5% of the Monte Carlo at 3-10 cm from the field edge and within a factor of 2 of the Monte Carlo at 10-20 cm from the field edge. Beyond 20 cm, the model poorly estimated H/DRx, however, the values were very small, at <0.03 mSv Gy-1.

Independent application of an analytical model for secondary neutron equivalent dose produced in a passive-scattering proton therapy treatment unit.

The purpose of this study was to independently apply an analytical model for equivalent dose from neutrons produced in a passive-scattering proton therapy treatment unit, H. To accomplish this objective, we applied the previously-published model to treatment plans of two pediatric patients. Their model accounted for neutrons generated by mono-energetic proton beams stopping in a closed aperture. To implement their model to a clinical setting, we adjusted it to account for the area of a collimating aperture, energy modulation, air gap between the treatment unit and patient, and radiation weighting factor. We used the adjusted model to estimate H per prescribed proton absorbed dose, D Rx , for the passive-scattering proton therapy beams of two children, a 9-year-old girl and 10-year-old boy, who each received intracranial boost fields as part of their treatment. In organs and tissues at risk for radiation-induced subsequent malignant neoplasms, T, we calculated the mass-averaged H, H T , per D Rx . Finally, we compared H T /D Rx values to those of previously-published Monte Carlo (MC) simulations of these patients' fields. H T /D Rx values of the adjusted model deviated from the MC result for each organ on average by 20.8 ± 10.0% and 44.2 ± 17.6% for the girl and boy, respectively. The adjusted model underestimated the MC result in all T of each patient, with the exception of the girl's bladder, for which the adjusted model overestimated H T /D Rx by 3.1%. The adjusted model provided a better estimate of H T /D Rx than the unadjusted model. That is, between the two models, the adjusted model reduced the deviation from the MC result by approximately 37.0% and 46.7% for the girl and boy, respectively. We found that the previously-published analytical model, combined with adjustment factors to enhance its clinical applicability, predicted H T /D Rx in out-of-field organs and tissues at risk for subsequent malignant neoplasms with acceptable accuracy. This independent application demonstrated that the analytical model may be useful broadly for clinicians and researchers to calculate equivalent dose from neutrons produced externally to the patient in passive-scattering proton therapy.

Low- and middle-income countries can reduce risks of subsequent neoplasms by referring pediatric craniospinal cases to centralized proton treatment centers.

Few children with cancer in low- and middle-income countries (LMICs) have access to proton therapy. Evidence exists to support replacing photon therapy with proton therapy to reduce the incidence of secondary malignant neoplasms (SMNs) in childhood cancer survivors. The purpose of this study was to estimate the potential reduction in SMN incidence and in SMN mortality for pediatric medulloblastoma patients in LMICs if proton therapy were made available to them. For nine children of ages 2 to 14 years, we calculated the equivalent dose in organs or tissues at risk for radiogenic SMNs from therapeutic and stray radiation for photon craniospinal irradiation (CSI) in a LMIC and proton CSI in a high-income country. We projected the lifetime risks of SMN incidence and SMN mortality for every SMN site with a widely-used model from the literature. We found that the average total lifetime attributable risks of incidence and mortality were very high for both photon CSI (168% and 41%, respectively) and proton CSI (88% and 26%, respectively). SMNs having the highest risk of mortality were lung cancer (16%), non-site-specific solid tumors (16%), colon cancer (5.9%), leukemia (5.4%), and for girls breast cancer (5.0%) after photon CSI and non-site-specific solid tumors (12%), lung cancer (11%), and leukemia (4.8%) after proton CSI. The risks were higher for younger children than for older children and higher for girls than for boys. The ratios of proton CSI to photon CSI of total risks of SMN incidence and mortality were 0.56 (95% CI, 0.37 to 0.75) and 0.64 (95% CI, 0.45 to 0.82), respectively, averaged over this sample group. In conclusion, proton therapy has the potential to lessen markedly subsequent SMNs and SMN fatalities in survivors of childhood medulloblastoma in LMICs, for example, through regional centralized care. Additional methods should be explored urgently to reduce therapeutic-field doses in organs and tissues at risk for SMN, especially in the lungs, colon, and breast tissues.

Supplemental computational phantoms to estimate out-of-field absorbed dose in photon radiotherapy.

The purpose of this study was to develop a straightforward method of supplementing patient anatomy and estimating out-of-field absorbed dose for a cohort of pediatric radiotherapy patients with limited recorded anatomy. A cohort of nine children, aged 2-14 years, who received 3D conformal radiotherapy for low-grade localized brain tumors (LBTs), were randomly selected for this study. The extent of these patients' computed tomography simulation image sets were cranial only. To approximate their missing anatomy, we supplemented the LBT patients' image sets with computed tomography images of patients in a previous study with larger extents of matched sex, height, and mass and for whom contours of organs at risk for radiogenic cancer had already been delineated. Rigid fusion was performed between the LBT patients' data and that of the supplemental computational phantoms using commercial software and in-house codes. In-field dose was calculated with a clinically commissioned treatment planning system, and out-of-field dose was estimated with a previously developed analytical model that was re-fit with parameters based on new measurements for intracranial radiotherapy. Mean doses greater than 1 Gy were found in the red bone marrow, remainder, thyroid, and skin of the patients in this study. Mean organ doses between 150 mGy and 1 Gy were observed in the breast tissue of the girls and lungs of all patients. Distant organs, i.e. prostate, bladder, uterus, and colon, received mean organ doses less than 150 mGy. The mean organ doses of the younger, smaller LBT patients (0-4 years old) were a factor of 2.4 greater than those of the older, larger patients (8-12 years old). Our findings demonstrated the feasibility of a straightforward method of applying supplemental computational phantoms and dose-calculation models to estimate absorbed dose for a set of children of various ages who received radiotherapy and for whom anatomies were largely missing in their original computed tomography simulations.

Reducing the cost of proton radiation therapy: the feasibility of a streamlined treatment technique for prostate cancer.

Proton radiation therapy is an effective modality for cancer treatments, but the cost of proton therapy is much higher compared to conventional radiotherapy and this presents a formidable barrier to most clinical practices that wish to offer proton therapy. Little attention in literature has been paid to the costs associated with collimators, range compensators and hypofractionation. The objective of this study was to evaluate the feasibility of cost-saving modifications to the present standard of care for proton treatments for prostate cancer. In particular, we quantified the dosimetric impact of a treatment technique in which custom fabricated collimators were replaced with a multileaf collimator (MLC) and the custom range compensators (RC) were eliminated. The dosimetric impacts of these modifications were assessed for 10 patients with a commercial treatment planning system (TPS) and confirmed with corresponding Monte Carlo simulations. We assessed the impact on lifetime risks of radiogenic second cancers using detailed dose reconstructions and predictive dose-risk models based on epidemiologic data. We also performed illustrative calculations, using an isoeffect model, to examine the potential for hypofractionation. Specifically, we bracketed plausible intervals of proton fraction size and total treatment dose that were equivalent to a conventional photon treatment of 79.2 Gy in 44 fractions. Our results revealed that eliminating the RC and using an MLC had negligible effect on predicted dose distributions and second cancer risks. Even modest hypofractionation strategies can yield substantial cost savings. Together, our results suggest that it is feasible to modify the standard of care to increase treatment efficiency, reduce treatment costs to patients and insurers, while preserving high treatment quality.

Inter-Institutional Comparison of Personalized Risk Assessments for Second Malignant Neoplasms for a 13-Year-Old Girl Receiving Proton versus Photon Craniospinal Irradiation.

Children receiving radiotherapy face the probability of a subsequent malignant neoplasm (SMN). In some cases, the predicted SMN risk can be reduced by proton therapy. The purpose of this study was to apply the most comprehensive dose assessment methods to estimate the reduction in SMN risk after proton therapy vs. photon therapy for a 13-year-old girl requiring craniospinal irradiation (CSI). We reconstructed the equivalent dose throughout the patient's body from therapeutic and stray radiation and applied SMN incidence and mortality risk models for each modality. Excluding skin cancer, the risk of incidence after proton CSI was a third of that of photon CSI. The predicted absolute SMN risks were high. For photon CSI, the SMN incidence rates greater than 10% were for thyroid, non-melanoma skin, lung, colon, stomach, and other solid cancers, and for proton CSI they were non-melanoma skin, lung, and other solid cancers. In each setting, lung cancer accounted for half the risk of mortality. In conclusion, the predicted SMN risk for a 13-year-old girl undergoing proton CSI was reduced vs. photon CSI. This study demonstrates the feasibility of inter-institutional whole-body dose and risk assessments and also serves as a model for including risk estimation in personalized cancer care.

A comparative study on the risks of radiogenic second cancers and cardiac mortality in a set of pediatric medulloblastoma patients treated with photon or proton craniospinal irradiation.

PURPOSE: To compare the risks of radiogenic second cancers and cardiac mortality in 17 pediatric medulloblastoma patients treated with passively scattered proton or field-in-field photon craniospinal irradiation (CSI). MATERIAL/METHODS: Standard of care photon or proton CSI treatment plans were created for all 17 patients in a commercial treatment planning system (TPS) (Eclipse version 8.9; Varian Medical Systems, Palo Alto, CA) and prescription dose was 23.4 or 23.4 Gy (RBE) to the age specific target volume at 1.8 Gy/fraction. The therapeutic doses from proton and photon CSI plans were estimated from TPS. Stray radiation doses were determined from Monte Carlo simulations for proton CSI and from measurements and TPS for photon CSI. The Biological Effects of Ionization Radiation VII report and a linear model based on childhood cancer survivor data were used for risk predictions of second cancer and cardiac mortality, respectively. RESULTS: The ratios of lifetime attributable risk (RLARs) (proton/photon) ranged from 0.10 to 0.22 for second cancer incidence and ranged from 0.20 to 0.53 for second cancer mortality, respectively. The ratio of relative risk (RRR) (proton/photon) of cardiac mortality ranged from 0.12 to 0.24. The RLARs of both cancer incidence and mortality decreased with patient's age at exposure (e), while the RRRs of cardiac mortality increased with e. Girls had a significantly higher RLAR of cancer mortality than boys. CONCLUSION: Passively scattered proton CSI provides superior predicted outcomes by conferring lower predicted risks of second cancer and cardiac mortality than field-in-field photon CSI for all medulloblastoma patients in a large clinically representative sample in the United States, but the magnitude of superiority depends strongly on the patients' anatomical development status.

Analytical model for out-of-field dose in photon craniospinal irradiation.

The prediction of late effects after radiotherapy in organs outside a treatment field requires accurate estimations of out-of-field dose. However, out-of-field dose is not calculated accurately by commercial treatment planning systems (TPSs). The purpose of this study was to develop and test an analytical model for out-of-field dose during craniospinal irradiation (CSI) from photon beams produced by a linear accelerator. In two separate evaluations of the model, we measured absorbed dose for a 6 MV CSI using thermoluminescent dosimeters placed throughout an anthropomorphic phantom and fit the measured data to an analytical model of absorbed dose versus distance outside of the composite field edge. These measurements were performed in two separate clinics-the University of Texas MD Anderson Cancer Center (MD Anderson) and the American University of Beirut Medical Center (AUBMC)-using the same phantom but different linear accelerators and TPSs commissioned for patient treatments. The measurement at AUBMC also included in-field locations. Measured dose values were compared to those predicted by TPSs and parameters were fit to the model in each setting. In each clinic, 95% of the measured data were contained within a factor of 0.2 and one root mean square deviation of the model-based values. The root mean square deviations of the mathematical model were 0.91 cGy Gy(-1) and 1.67 cGy Gy(-1) in the MD Anderson and AUBMC clinics, respectively. The TPS predictions agreed poorly with measurements in regions of sharp dose gradient, e.g., near the field edge. At distances greater than 1 cm from the field edge, the TPS underestimated the dose by an average of 14% ± 24% and 44% ± 19% in the MD Anderson and AUBMC clinics, respectively. The in-field measured dose values of the measurement at AUBMC matched the dose values calculated by the TPS to within 2%. Dose algorithms in TPSs systematically underestimated the actual out-of-field dose. Therefore, it is important to use an improved model based on measurements when estimating out-of-field dose. The model proposed in this study performed well for this purpose in two clinics and may be applicable in other clinics with similar treatment field configurations.

Predicted risks of radiogenic cardiac toxicity in two pediatric patients undergoing photon or proton radiotherapy.

BACKGROUND: Hodgkin disease (HD) and medulloblastoma (MB) are common malignancies found in children and young adults, and radiotherapy is part of the standard treatment. It was reported that these patients who received radiation therapy have an increased risk of cardiovascular late effects. We compared the predicted risk of developing radiogenic cardiac toxicity after photon versus proton radiotherapies for a pediatric patient with HD and a pediatric patient with MB. METHODS: In the treatment plans, each patient's heart was contoured in fine detail, including substructures of the pericardium and myocardium. Risk calculations took into account both therapeutic and stray radiation doses. We calculated the relative risk (RR) of cardiac toxicity using a linear risk model and the normal tissue complication probability (NTCP) values using relative seriality and Lyman models. Uncertainty analyses were also performed. RESULTS: The RR values of cardiac toxicity for the HD patient were 7.27 (proton) and 8.37 (photon), respectively; the RR values for the MB patient were 1.28 (proton) and 8.39 (photon), respectively. The predicted NTCP values for the HD patient were 2.17% (proton) and 2.67% (photon) for the myocardium, and were 2.11% (proton) and 1.92% (photon) for the whole heart. The predicted ratios of NTCP values (proton/photon) for the MB patient were much less than unity. Uncertainty analyses revealed that the predicted ratio of risk between proton and photon therapies was sensitive to uncertainties in the NTCP model parameters and the mean radiation weighting factor for neutrons, but was not sensitive to heart structure contours. The qualitative findings of the study were not sensitive to uncertainties in these factors. CONCLUSIONS: We conclude that proton and photon radiotherapies confer similar predicted risks of cardiac toxicity for the HD patient in this study, and that proton therapy reduced the predicted risk for the MB patient in this study.

Comparison of risk of radiogenic second cancer following photon and proton craniospinal irradiation for a pediatric medulloblastoma patient.

Pediatric patients who received radiation therapy are at risk of developing side effects such as radiogenic second cancer. We compared proton and photon therapies in terms of the predicted risk of second cancers for a 4 year old medulloblastoma patient receiving craniospinal irradiation (CSI). Two CSI treatment plans with 23.4 Gy or Gy (RBE) prescribed dose were computed: a three-field 6 MV photon therapy plan and a four-field proton therapy plan. The primary doses for both plans were determined using a commercial treatment planning system. Stray radiation doses for proton therapy were determined from Monte Carlo simulations, and stray radiation doses for photon therapy were determined from measured data. Dose-risk models based on the Biological Effects of Ionization Radiation VII report were used to estimate the risk of second cancer in eight tissues/organs. Baseline predictions of the relative risk for each organ were always less for proton CSI than for photon CSI at all attained ages. The total lifetime attributable risk of the incidence of second cancer considered after proton CSI was much lower than that after photon CSI, and the ratio of lifetime risk was 0.18. Uncertainty analysis revealed that the qualitative findings of this study were insensitive to any plausible changes of dose-risk models and mean radiation weighting factor for neutrons. Proton therapy confers lower predicted risk of second cancer than photon therapy for the pediatric medulloblastoma patient.

External-beam accelerated partial breast irradiation using multiple proton beam configurations.

PURPOSE: To explore multiple proton beam configurations for optimizing dosimetry and minimizing uncertainties for accelerated partial breast irradiation (APBI) and to compare the dosimetry of proton with that of photon radiotherapy for treatment of the same clinical volumes. METHODS AND MATERIALS: Proton treatment plans were created for 11 sequential patients treated with three-dimensional radiotherapy (3DCRT) photon APBI using passive scattering proton beams (PSPB) and were compared with clinically treated 3DCRT photon plans. Monte Carlo calculations were used to verify the accuracy of the proton dose calculation from the treatment planning system. The impact of range, motion, and setup uncertainty was evaluated with tangential vs. en face beams. RESULTS: Compared with 3DCRT photons, the absolute reduction of the mean of V100 (the volume receiving 100% of prescription dose), V90, V75, V50, and V20 for normal breast using protons are 3.4%, 8.6%, 11.8%, 17.9%, and 23.6%, respectively. For breast skin, with the similar V90 as 3DCRT photons, the proton plan significantly reduced V75, V50, V30, and V10. The proton plan also significantly reduced the dose to the lung and heart. Dose distributions from Monte Carlo simulations demonstrated minimal deviation from the treatment planning system. The tangential beam configuration showed significantly less dose fluctuation in the chest wall region but was more vulnerable to respiratory motion than that for the en face beams. Worst-case analysis demonstrated the robustness of designed proton beams with range and patient setup uncertainties. CONCLUSIONS: APBI using multiple proton beams spares significantly more normal tissue, including nontarget breast and breast skin, than 3DCRT using photons. It is robust, considering the range and patient setup uncertainties.

Predicted risks of second malignant neoplasm incidence and mortality due to secondary neutrons in a girl and boy receiving proton craniospinal irradiation.

The purpose of this study was to compare the predicted risks of second malignant neoplasm (SMN) incidence and mortality from secondary neutrons for a 9-year-old girl and a 10-year-old boy who received proton craniospinal irradiation (CSI). SMN incidence and mortality from neutrons were predicted from equivalent doses to radiosensitive organs for cranial, spinal and intracranial boost fields. Therapeutic proton absorbed dose and equivalent dose from neutrons were calculated using Monte Carlo simulations. Risks of SMN incidence and mortality in most organs and tissues were predicted by applying risks models from the National Research Council of the National Academies to the equivalent dose from neutrons; for non-melanoma skin cancer, risk models from the International Commission on Radiological Protection were applied. The lifetime absolute risks of SMN incidence due to neutrons were 14.8% and 8.5%, for the girl and boy, respectively. The risks of a fatal SMN were 5.3% and 3.4% for the girl and boy, respectively. The girl had a greater risk for any SMN except colon and liver cancers, indicating that the girl's higher risks were not attributable solely to greater susceptibility to breast cancer. Lung cancer predominated the risk of SMN mortality for both patients. This study suggests that the risks of SMN incidence and mortality from neutrons may be greater for girls than for boys treated with proton CSI.

A GPU implementation of a track-repeating algorithm for proton radiotherapy dose calculations.

An essential component in proton radiotherapy is the algorithm to calculate the radiation dose to be delivered to the patient. The most common dose algorithms are fast but they are approximate analytical approaches. However their level of accuracy is not always satisfactory, especially for heterogeneous anatomical areas, like the thorax. Monte Carlo techniques provide superior accuracy; however, they often require large computation resources, which render them impractical for routine clinical use. Track-repeating algorithms, for example the fast dose calculator, have shown promise for achieving the accuracy of Monte Carlo simulations for proton radiotherapy dose calculations in a fraction of the computation time. We report on the implementation of the fast dose calculator for proton radiotherapy on a card equipped with graphics processor units (GPUs) rather than on a central processing unit architecture. This implementation reproduces the full Monte Carlo and CPU-based track-repeating dose calculations within 2%, while achieving a statistical uncertainty of 2% in less than 1 min utilizing one single GPU card, which should allow real-time accurate dose calculations.

Adjustment of the lateral and longitudinal size of scanned proton beam spots using a pre-absorber to optimize penumbrae and delivery efficiency.

In scanned-beam proton therapy, the beam spot properties, such as the lateral and longitudinal size and the minimum achievable range, are influenced by beam optics, scattering media and drift spaces in the treatment unit. Currently available spot scanning systems offer few options for adjusting these properties. We investigated a method for adjusting the lateral and longitudinal spot size that utilizes downstream plastic pre-absorbers located near a water phantom. The spot size adjustment was characterized using Monte Carlo simulations of a modified commercial scanned-beam treatment head. Our results revealed that the pre-absorbers can be used to reduce the lateral full width at half maximum (FWHM) of dose spots in water by up to 14 mm, and to increase the longitudinal extent from about 1 mm to 5 mm at residual ranges of 4 cm and less. A large factor in manipulating the lateral spot sizes is the drift space between the pre-absorber and the water phantom. Increasing the drift space from 0 cm to 15 cm leads to an increase in the lateral FWHM from 2.15 cm to 2.87 cm, at a water-equivalent depth of 1 cm. These findings suggest that this spot adjustment method may improve the quality of spot-scanned proton treatments.

Methodology for determining doses to in-field, out-of-field and partially in-field organs for late effects studies in photon radiotherapy.

An important but little examined aspect of radiation dosimetry studies involving organs outside the treatment field is how to assess dose to organs that are partially within a treatment field; this question is particularly important for studies intended to measure total absorbed dose in order to predict the risk of radiogenic late effects, such as second cancers. The purpose of this investigation was therefore to establish a method to categorize organs as in-field, out-of-field or partially in-field that would be applicable to both conventional and modern radiotherapy techniques. In this study, we defined guidelines to categorize the organs based on isodose inclusion criteria, developed methods to assess doses to partially in-field organs, and then tested the methods by applying them to a case of intensity-modulated radiotherapy for hepatocellular carcinoma based on actual patient data. For partially in-field organs, we recommend performing a sensitivity test to determine whether potential inaccuracies in low-dose regions of the DVH (from the treatment planning system) have a substantial effect on the mean organ dose, i.e. >5%. In such cases, we suggest supplementing calculated DVH data with measured dosimetric data using a volume-weighting technique to determine the mean dose.

Assessment of targeting accuracy of a low-energy stereotactic radiosurgery treatment for age-related macular degeneration.

Age-related macular degeneration (AMD), a leading cause of blindness in the United States, is a neovascular disease that may be controlled with radiation therapy. Early patient outcomes of external beam radiotherapy, however, have been mixed. Recently, a novel multimodality treatment was developed, comprising external beam radiotherapy and concomitant treatment with a vascular endothelial growth factor inhibitor. The radiotherapy arm is performed by stereotactic radiosurgery, delivering a 16 Gy dose in the macula (clinical target volume, CTV) using three external low-energy x-ray fields while adequately sparing normal tissues. The purpose of our study was to test the sensitivity of the delivery of the prescribed dose in the CTV using this technique and of the adequate sparing of normal tissues to all plausible variations in the position and gaze angle of the eye. Using Monte Carlo simulations of a 16 Gy treatment, we varied the gaze angle by ±5° in the polar and azimuthal directions, the linear displacement of the eye ±1 mm in all orthogonal directions, and observed the union of the three fields on the posterior wall of spheres concentric with the eye that had diameters between 20 and 28 mm. In all cases, the dose in the CTV fluctuated <6%, the maximum dose in the sclera was <20 Gy, the dose in the optic disc, optic nerve, lens and cornea were <0.7 Gy and the three-field junction was adequately preserved. The results of this study provide strong evidence that for plausible variations in the position of the eye during treatment, either by the setup error or intrafraction motion, the prescribed dose will be delivered to the CTV and the dose in structures at risk will be kept far below tolerance doses.