Double-strand breaks measured along a 160 MeV proton Bragg curve using a novel FIESTA-DNA probe in a cell-free environment.

Proton radiotherapy treatment planning systems use a constant relative biological effectiveness (RBE) = 1.1 to convert proton absorbed dose into biologically equivalent high-energy photon dose. This method ignores linear energy transfer (LET) distributions, and RBE is known to change as a function of LET. Variable RBE approaches have been proposed for proton planning optimization. Experimental validation of models underlying these approaches is a pre-requisite for their clinical implementation. This validation has to probe every level in the evolution of radiation-induced biological damage leading to cell death, starting from DNA double-strand breaks (DSB). Using a novel FIESTA-DNA probe, we measured the probability of double-strand break (P DSB) along a 160 MeV proton Bragg curve at two dose levels (30 and 60 Gy (RBE)) and compared it to measurements in a 6 MV photon beam. A machined setup that held an Advanced Markus parallel plate chamber for proton dose verification alongside the probes was fabricated. Each sample set consisted of five 10 µl probes suspended inside plastic microcapillary tubes. These were irradiated with protons to 30 Gy (RBE) at depths of 5-17.5 cm and 60 Gy (RBE) at depths of 10-17.2 cm with 1 mm resolution around Bragg peak. Sample sets were also irradiated using 6MV photons to 20, 40, 60, and 80 Gy. For the 30 Gy (RBE) measurements, increases in P DSB/Gy were observed at 17.0 cm followed by decreases at larger depth. For the 60 Gy (RBE) measurements, no increase in P DSB/Gy was observed, but there was a decrease after 17.0 cm. Dose-response for P DSB between 30 and 60 Gy (RBE) showed less than doubling of P DSB when dose was doubled. Proton RBE effect from DSB, RBEP,DSB, was <1 except at the Bragg peak. The experiment showed that the novel probe can be used to perform DNA DSB measurements in a proton beam. To establish relevance to clinical environment, further investigation of the probe's chemical scavenging needs to be performed.

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.

A Dosimetric Comparison of Intensity-Modulated Proton Therapy, Volumetric-Modulated Arc Therapy, and 4π Non-Coplanar Intensity-Modulated Radiation Therapy for a Patient with Parameningeal Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and manifests as two major histological subtypes: embryonal and alveolar. The five-year local failure rate for RMS at parameningeal sites (middle ear, mastoid region, nasal cavity, etc.) is around 17% despite multiple Intergroup Rhabdomyosarcoma Study Group (IRS) trials conducted to determine the optimal radiation treatment regimen. This case report explores the use of intensity-modulated proton therapy (IMPT) for a 10-year-old child who presented with left eye irritation, facial pain, and headaches and was found to have an alveolar parameningeal rhabdomyosarcoma. He received systemic therapy as well as radiation therapy to 5,640 cGy and 4,320 cGy over 24 fractions, prescribed for gross tumor extension and adjacent high-risk involved sites, respectively, via simultaneous integrated boost. Approximately two years following treatment, the patient has had no recurrence of his RMS with no distant metastases. In addition, his presenting symptom of left eye irritation has improved. His only side effect from radiation at this point is short stature, possibly due to growth hormone deficiency. The patient's IMPT plan was compared with volumetric-modulated arc therapy (VMAT) and 4π non-coplanar intensity-modulated radiation therapy (IMRT) plans, and comparisons of isodose lines show decreased dose to the distal brain tissue with preserved target conformality by IMPT. IMPT also allowed for increased sparing of the patient's retina, lens, and lacrimal gland. All radiation plans achieved conformal dose coverage to the planning/scanning target volumes, while the IMPT plan is potentially better at sparing the patient from developing long-term optic apparatus side effects and neurocognitive defects. In this case, IMPT is comparable, if not favorable, when long-term side effects can be reduced while maintaining dose conformality and local control.

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.

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.

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.

Standardized treatment planning methodology for passively scattered proton craniospinal irradiation.

BACKGROUND: As the number of proton therapy centers increases, so does the need for studies which compare proton treatments between institutions and with photon therapy. However, results of such studies are highly dependent on target volume definition and treatment planning techniques. Thus, standardized methods of treatment planning are needed, particularly for proton treatment planning, in which special consideration is paid to the depth and sharp distal fall-off of the proton distribution. This study presents and evaluates a standardized method of proton treatment planning for craniospinal irradiation (CSI). METHODS: We applied our institution's planning methodology for proton CSI, at the time of the study, to an anatomically diverse population of 18 pediatric patients. We evaluated our dosimetric results for the population as a whole and for the two subgroups having two different age-specific target volumes using the minimum, maximum, and mean dose values in 10 organs (i.e., the spinal cord, brain, eyes, lenses, esophagus, lungs, kidneys, thyroid, heart, and liver). We also report isodose distributions and dose-volume histograms (DVH) for 2 representative patients. Additionally we report population-averaged DVHs for various organs. RESULTS: The planning methodology here describes various techniques used to achieve normal tissue sparing. In particular, we found pronounced dose reductions in three radiosensitive organs (i.e., eyes, esophagus, and thyroid) which were identified for optimization. Mean doses to the thyroid, eyes, and esophagus were 0.2%, 69% and 0.2%, respectively, of the prescribed dose. In four organs not specifically identified for optimization (i.e., lungs, liver, kidneys, and heart) we found that organs lateral to the treatment field (lungs and kidneys) received relatively low mean doses (less than 8% of the prescribed dose), whereas the heart and liver, organs distal to the treatment field, received less than 1% of the prescribed dose. CONCLUSIONS: This study described and evaluated a standardized method for proton treatment planning for CSI. Overall, the standardized planning methodology yielded consistently high quality treatment plans and perhaps most importantly, it did so for an anatomically diverse patient population.

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.

Comparison of therapeutic dosimetric data from passively scattered proton and photon craniospinal irradiations for medulloblastoma.

BACKGROUND: For many decades, the standard of care radiotherapy regimen for medulloblastoma has been photon (megavoltage x-rays) craniospinal irradiation (CSI). The late effects associated with CSI are well-documented in the literature and are in-part attributed to unwanted dose to healthy tissue. Recently, there is growing interest in using proton therapy for CSI in pediatric and adolescent patients to reduce this undesirable dose. Previous comparisons of dose to target and non-target organs from conventional photon CSI and passively scattered proton CSI have been limited to small populations (n ≤ 3) and have not considered the use of age-dependent target volumes in proton CSI. METHODS: Standard of care treatment plans were developed for both photon and proton CSI for 18 patients. This cohort included both male and female medulloblastoma patients whose ages, heights, and weights spanned a clinically relevant and representative spectrum (age 2-16, BMI 16.4-37.9 kg/m2). Differences in plans were evaluated using Wilcoxon signed rank tests for various dosimetric parameters for the target volumes and normal tissue. RESULTS: Proton CSI improved normal tissue sparing while also providing more homogeneous target coverage than photon CSI for patients across a wide age and BMI spectrum. Of the 24 parameters (V5, V10, V15, and V20 in the esophagus, heart, liver, thyroid, kidneys, and lungs) Wilcoxon signed rank test results indicated 20 were significantly higher for photon CSI compared to proton CSI (p ≤ 0.05) . Specifically, V15 and V20 in all six organs and V5, V10 in the esophagus, heart, liver, and thyroid were significantly higher with photon CSI. CONCLUSIONS: Our patient cohort is the largest, to date, in which CSI with proton and photon therapies have been compared. This work adds to the body of literature that proton CSI reduces dose to normal tissue compared to photon CSI for pediatric patients who are at substantial risk for developing radiogenic late effects. Although the present study focused on medulloblastoma, our findings are generally applicable to other tumors that are treated with CSI.

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.

Stray radiation dose and second cancer risk for a pediatric patient receiving craniospinal irradiation with proton beams.

Proton beam radiotherapy unavoidably exposes healthy tissue to stray radiation emanating from the treatment unit and secondary radiation produced within the patient. These exposures provide no known benefit and may increase a patient's risk of developing a radiogenic cancer. The aims of this study were to calculate doses to major organs and tissues and to estimate second cancer risk from stray radiation following craniospinal irradiation (CSI) with proton therapy. This was accomplished using detailed Monte Carlo simulations of a passive-scattering proton treatment unit and a voxelized phantom to represent the patient. Equivalent doses, effective dose and corresponding risk for developing a fatal second cancer were calculated for a 10-year-old boy who received proton therapy. The proton treatment comprised CSI at 30.6 Gy plus a boost of 23.4 Gy to the clinical target volume. The predicted effective dose from stray radiation was 418 mSv, of which 344 mSv was from neutrons originating outside the patient; the remaining 74 mSv was caused by neutrons originating within the patient. This effective dose corresponds to an attributable lifetime risk of a fatal second cancer of 3.4%. The equivalent doses that predominated the effective dose from stray radiation were in the lungs, stomach and colon. These results establish a baseline estimate of the stray radiation dose and corresponding risk for a pediatric patient undergoing proton CSI and support the suitability of passively-scattered proton beams for the treatment of central nervous system tumors in pediatric patients.

Dose perturbations from implanted helical gold markers in proton therapy of prostate cancer.

Implanted gold fiducial markers are widely used in radiation therapy to improve targeting accuracy. Recent investigations have revealed that metallic fiducial markers can cause severe perturbations in dose distributions for proton therapy, suggesting smaller markers should be considered. The objective of this study was to estimate the dosimetric impact of small gold markers in patients receiving proton therapy for prostate cancer. Small, medium, and large helical wire markers with lengths of 10 mm and helix diameters of 0.35 mm, 0.75 mm, and 1.15 mm, respectively, were implanted in an anthropomorphic phantom. Radiographic visibility was confirmed using a kilovoltage x-ray imaging system, and dose perturbations were predicted from Monte Carlo simulations and confirmed by measurements. Monte Carlo simulations indicated that size of dose perturbation depended on marker size, orientation, and distance from the beam's end of range. Specifically, the perturbation of proton dose for the lateral-opposed-pair treatment technique was 31% for large markers and 23% for medium markers in a typical oblique orientation. Results for perpendicular and parallel orientations were respectively lower and higher. Consequently, these markers are not well suited for use in patients receiving proton therapy for prostate cancer. Dose perturbation was not observed for the small markers, but these markers were deemed too fragile for transrectal implantation in the prostate.

Contemporary Proton Therapy Systems Adequately Protect Patients from Exposure to Stray Radiation.

Proton beam therapy has provided safe and effective treatments for a variety of adult cancers. In recent years, there has been increasing interest in utilizing proton therapy for pediatric cancers because it allows better sparing of healthy tissues. Minimizing exposures of normal tissues is especially important in children because they are highly susceptible to consequential late effects, including the development of a radiogenic second cancer, which may occur years or even decades after treatment of the first cancer. While the dosimetric advantage of therapeutic proton beams is well understood, relatively little attention has been paid to the whole-body exposure to stray neutron radiation that is inherent in proton therapy. In this report, we review the physical processes that lead to neutron exposures, discuss the potential for mitigating these exposures using advanced proton beam delivery systems, and present a comparative analysis of predicted second cancer incidence following various external beam therapies. In addition, we discuss uncertainties in the relative biological effectiveness of neutrons for carcinogenesis and the impact that these uncertainties have on second-cancer risk predictions for survivors of adult and childhood cancer who receive proton therapy.

REDUCING STRAY RADIATION DOSE FOR A PEDIATRIC PATIENT RECEIVING PROTON CRANIOSPINAL IRRADIATION.

The aim of this study was to quantify stray radiation dose from neutrons emanating from a proton treatment unit and to evaluate methods of reducing this dose for a pediatric patient undergoing craniospinal irradiation. The organ equivalent doses and effective dose from stray radiation were estimated for a 30.6-Gy treatment using Monte Carlo simulations of a passive scattering treatment unit and a patient-specific voxelized anatomy. The treatment plan was based on computed tomography images of a 10-yr-old male patient. The contribution to stray radiation was evaluated for the standard nozzle and for the same nozzle but with modest modifications to suppress stray radiation. The modifications included enhancing the local shielding between the patient and the primary external neutron source and increasing the distance between them. The effective dose from stray radiation emanating from the standard nozzle was 322 mSv; enhancements to the nozzle reduced the effective dose by as much as 43%. These results add to the body of evidence that modest enhancements to the treatment unit can reduce substantially the effective dose from stray radiation.

Can megavoltage computed tomography reduce proton range uncertainties in treatment plans for patients with large metal implants?

Treatment planning calculations for proton therapy require an accurate knowledge of radiological path length, or range, to the distal edge of the target volume. In most cases, the range may be calculated with sufficient accuracy using kilovoltage (kV) computed tomography (CT) images. However, metal implants such as hip prostheses can cause severe streak artifacts that lead to large uncertainties in proton range. The purposes of this study were to quantify streak-related range errors and to determine if they could be avoided by using artifact-free megavoltage (MV) CT images in treatment planning. Proton treatment plans were prepared for a rigid, heterogeneous phantom and for a prostate cancer patient with a metal hip prosthesis using corrected and uncorrected kVCT images alone, uncorrected MVCT images and a combination of registered MVCT and kVCT images (the hybrid approach). Streak-induced range errors of 5-12 mm were present in the uncorrected kVCT-based patient plan. Correcting the streaks by manually assigning estimated true Hounsfield units improved the range accuracy. In a rigid heterogeneous phantom, the implant-related range uncertainty was estimated at <3 mm for both the corrected kVCT-based plan and the uncorrected MVCT-based plan. The hybrid planning approach yielded the best overall result. In this approach, the kVCT images provided good delineation of soft tissues due to high-contrast resolution, and the streak-free MVCT images provided smaller range uncertainties because they did not require artifact correction.