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Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Rationale and Framework for the Monograph and Overview of Eligible Studies

Abstract Whether low-dose ionizing radiation can cause cancer is a critical and long-debated question in radiation protection. Since the Biological Effects of Ionizing Radiation report by the National Academies in 2006, new publications from large, well-powered epidemiological studies of low doses have reported positive dose-response relationships. It has been suggested, however, that biases could explain these findings. We conducted a systematic review of epidemiological studies with mean doses less than 100 mGy published 2006–2017. We required individualized doses and dose-response estimates with confidence intervals. We identified 26 eligible studies (eight environmental, four medical, and 14 occupational), including 91 000 solid cancers and 13 000 leukemias. Mean doses ranged from 0.1 to 82 mGy. The excess relative risk at 100 mGy was positive for 16 of 22 solid cancer studies and 17 of 20 leukemia studies. The aim of this monograph was to systematically review the potential biases in these studies (including dose uncertainty, confounding, and outcome misclassification) and to assess whether the subset of minimally biased studies provides evidence for cancer risks from low-dose radiation. Here, we describe the framework for the systematic bias review and provide an overview of the eligible studies.

Berrington de Gonzalez, Amy↗

Use of Monte Carlo simulations with a realistic rat phantom for examining the correlation between hematopoietic system response and red marrow absorbed dose in Brown Norway rats undergoing radionuclide therapy with {sup 177}Lu- and {sup 90}Y-BR96 mAbs

Purpose: Biokinetic and dosimetry studies in laboratory animals often precede clinical radionuclide therapies in humans. A reliable evaluation of therapeutic efficacy is essential and should be based on accurate dosimetry data from a realistic dosimetry model. The aim of this study was to develop an anatomically realistic dosimetry model for Brown Norway rats to calculate S factors for use in evaluating correlations between absorbed dose and biological effects in a preclinical therapy study. Methods: A realistic rat phantom (Roby) was used, which has some flexibility that allows for a redefinition of organ sizes. The phantom was modified to represent the anatomic geometry of a Brown Norway rat, which was used for Monte Carlo calculations of S factors. Kinetic data for radiolabeled BR96 monoclonal antibodies were used to calculate the absorbed dose. Biological data were gathered from an activity escalation study with {sup 90}Y- and {sup 177}Lu-labeled BR96 monoclonal antibodies, in which blood cell counts and bodyweight were examined up to 2 months follow-up after injection. Reductions in white blood cell and platelet counts and declines in bodyweight were quantified by four methods and compared to the calculated absorbed dose to the bone marrow or the total body. Results: A red marrow absorbed dose-dependent effect on hematological parameters was observed, which could be evaluated by a decrease in blood cell counts. The absorbed dose to the bone marrow, corresponding to the maximal tolerable activity that could safely be administered, was determined to 8.3 Gy for {sup 177}Lu and 12.5 Gy for {sup 90}Y. Conclusions: There was a clear correlation between the hematological effects, quantified with some of the studied parameters, and the calculated red marrow absorbed doses. The decline in body weight was stronger correlated to the total body absorbed dose, rather than the red marrow absorbed dose. Finally, when considering a constant activity concentration, the phantom weight, ranging from 225 g to 300 g, appeared to have no substantial effect for the estimated absorbed dose.

61 RADIATION PROTECTION AND DOSIMETRY↗

Dose ratio proton radiography using the proximal side of the Bragg peak

Purpose: In recent years, there has been a movement toward single-detector proton radiography, due to its potential ease of implementation within the clinical environment. One such single-detector technique is the dose ratio method in which the dose maps from two pristine Bragg peaks are recorded beyond the patient. To date, this has only been investigated on the distal side of the lower energy Bragg peak, due to the sharp falloff. The authors investigate the limits and applicability of the dose ratio method on the proximal side of the lower energy Bragg peak, which has the potential to allow a much wider range of water-equivalent thicknesses (WET) to be imaged. Comparisons are made with the use of the distal side of the Bragg peak. Methods: Using the analytical approximation for the Bragg peak, the authors generated theoretical dose ratio curves for a range of energy pairs, and then determined how an uncertainty in the dose ratio would translate to a spread in the WET estimate. By defining this spread as the accuracy one could achieve in the WET estimate, the authors were able to generate lookup graphs of the range on the proximal side of the Bragg peak that one could reliably use. These were dependent on the energy pair, noise level in the dose ratio image and the required accuracy in the WET. Using these lookup graphs, the authors investigated the applicability of the technique for a range of patient treatment sites. The authors validated the theoretical approach with experimental measurements using a complementary metal oxide semiconductor active pixel sensor (CMOS APS), by imaging a small sapphire sphere in a high energy proton beam. Results: Provided the noise level in the dose ratio image was 1% or less, a larger spread of WETs could be imaged using the proximal side of the Bragg peak (max 5.31 cm) compared to the distal side (max 2.42 cm). In simulation, it was found that, for a pediatric brain, it is possible to use the technique to image a region with a square field equivalent size of 7.6 cm{sup 2}, for a required accuracy in the WET of 3 mm and a 1% noise level in the dose ratio image. The technique showed limited applicability for other patient sites. The CMOS APS demonstrated a good accuracy, with a root-mean-square-error of 1.6 mm WET. The noise in the measured images was found to be σ = 1.2% (standard deviation) and theoretical predictions with a 1.96σ noise level showed good agreement with the measured errors. Conclusions: After validating the theoretical approach with measurements, the authors have shown that the use of the proximal side of the Bragg peak when performing dose ratio imaging is feasible, and allows for a wider dynamic range than when using the distal side. The dynamic range available increases as the demand on the accuracy of the WET decreases. The technique can only be applied to clinical sites with small maximum WETs such as for pediatric brains.

60 APPLIED LIFE SCIENCES↗

WE-EF-BRA-03: Catheter- Free Ablation with External Photon Radiation: Treatment Planning, Delivery Considerations, and Correlation of Effects with Delivered Dose

Purpose: To plan, target, and calculate delivered dose in atrioventricular node (AVN) ablation with volume-modulated arc therapy (VMAT) in an intact porcine model. Methods: Seven pigs underwent AVN irradiation, with prescription doses ranging between 25 and 55Gy in a single fraction. Cardiac CT scans were acquired at expiration. Two physicians contoured AVN targets on 10 phases, providing estimates of target motion and inter-physician variability. Treatment planning was conducted on a static phase-averaged CT. The volume designated to receive prescription dose covered the full extent of AVN cardiac motion, expanded by 4mm for setup uncertainty. Optimization limited doses to risk structures according to single-fraction tumor treatment protocols. Orthogonal kV images were used to align bony anatomy at time of treatment. Localization was further refined with respiratory-gated cone-beam CT, and range of cardiac motion was verified under fluoroscopy. Beam delivery was respiratory-gated for expiration with a mean efficiency of 60%. Deformable registration of the 10 cardiac CT phases was used to calculate actual delivered dose for comparison to electro-anatomical and visually evident lesions. Results: The mean [minimum,maximum] amplitude of AVN cardiac motion was LR 2.9 [1.7,3.9]mm, AP 6.6 [4.4,10.4]mm, and SI 5.6 [2.0,9.9]mm. Incorporating cardiac motion into the dose calculation showed the volume receiving full dose was 40–80% of the volume indicated on the static planning image, although the contoured AVN target received full dose in all animals. Initial results suggest the dimensions of the electro-anatomical lesion are correlated with the 40Gy isodose volume. Conclusion: Image-guidance techniques allow for accurate and precise delivery of VMAT for catheter-free arrhythmia ablation. An arsenal of advanced radiation planning, dose optimization, and image-guided delivery techniques was employed to assess and mitigate effects of cardiac and respiratory motion. Feasibility of delivery to the pulmonary veins and left ventricular myocardium will be investigated in future studies. D. Packer Disclosures: Abiomed, Biosense Webster, Inc., Boston Scientific Corp., CardioFocus, Inc., Johnson and Johnson, Excerpta Medica, Ortho-McNeil-Jannsen, Sanofi Aventis, CardioInsight Technologies, InfoBionic, SIEMENS, Medtronic, Inc., CardioDx, Inc., CardioInsight Technologies, FoxP2 Medica, Mediasphere Medical, Wiley-Blackwell, St. Jude Medical, Endosense, Thermedical, EP Advocate LLC, Hansen Medical, American Heart Association, EpiEP, NIH.

60 APPLIED LIFE SCIENCES↗

SU-C-201-03: Ionization Chamber Collection Efficiency in Pulsed Radiation Fields of High Pulse Dose

Purpose: To investigate the reduction of collection efficiency of ionization chambers (IC) by volume recombination and its correction in pulsed fields of very high pulse dose. Methods: Measurements of the collection efficiency of a plane-parallel advanced Markus IC (PTW 34045, 1mm electrode spacing, 300V nominal voltage) were obtained for collection voltages of 100V and 300V by irradiation with a pulsed electron beam (20MeV) of varied pulse dose up to approximately 600mGy (0.8nC liberated charge). A reference measurement was performed with a Faraday cup behind the chamber. It was calibrated for the liberated charge in the IC by a linear fit of IC measurement to reference measurement at low pulse doses. The results were compared to the commonly used two voltage approximation (TVA) and to established theories for volume recombination, with and without considering a fraction of free electrons. In addition, an equation system describing the charge transport and reactions in the chamber was solved numerically. Results: At 100V collection voltage and moderate pulse doses the established theories accurately predict the observed collection efficiency, but at extreme pulse doses a fraction of free electrons needs to be considered. At 300V the observed collection efficiency deviates distinctly from that predicted by any of the established theories, even at low pulse doses. However, the numeric solution of the equation system is able to reproduce the measured collection efficiency across the entire dose range of both voltages with a single set of parameters. Conclusion: At high electric fields (3000V/cm here) the existing theoretical descriptions of collection efficiency, including the TVA, are inadequate to predict pulse dose dependency. Even at low pulse doses they might underestimate collection efficiency. The presented, more accurate numeric solution, which considers additional effects like electric shielding by the charges, might provide a valuable tool for future investigations. This project was funded by the German ministry of research and education (BMBF) under grant number: 03Z1N511 and by the state of Saxony under grant number: B 209.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

A Single Whole-Body Low Dose X-Irradiation Does Not Affect L1, B1 and IAP Repeat Element DNA Methylation Longitudinally

The low dose radioadaptive response has been shown to be protective against high doses of radiation as well as aging-induced genomic instability. We hypothesised that a single whole-body exposure of low dose radiation would induce a radioadaptive response thereby reducing or abrogating aging-related changes in repeat element DNA methylation in mice. Following sham or 10 mGy X-irradiation, serial peripheral blood sampling was performed and differences in Long Interspersed Nucleic Element 1 (L1), B1 and Intracisternal-A-Particle (IAP) repeat element methylation between samples were assessed using high resolution melt analysis of PCR amplicons. By 420 days post-irradiation, neither radiation- or aging-related changes in the methylation of peripheral blood, spleen or liver L1, B1 and IAP elements were observed. Analysis of the spleen and liver tissues of cohorts of untreated aging mice showed that the 17–19 month age group exhibited higher repeat element methylation than younger or older mice, with no overall decline in methylation detected with age. This is the first temporal analysis of the effect of low dose radiation on repeat element methylation in mouse peripheral blood and the first to examine the long term effect of this dose on repeat element methylation in a radiosensitive tissue (spleen) and a tissue fundamental to the aging process (liver). Our data indicate that the methylation of murine DNA repeat elements can fluctuate with age, but unlike human studies, do not demonstrate an overall aging-related decline. Furthermore, our results indicate that a low dose of ionising radiation does not induce detectable changes to murine repeat element DNA methylation in the tissues and at the time-points examined in this study. This radiation dose is relevant to human diagnostic radiation exposures and suggests that a dose of 10 mGy X-rays, unlike high dose radiation, does not cause significant short or long term changes to repeat element or global DNA methylation.

59 BASIC BIOLOGICAL SCIENCES↗

Application of FISH based G2-PCC assay for the cytogenetic assessment of high radiation dose exposures: Potential implications for rapid triage biodosimetry

The main goal of this study is to test the utility of calyculin A induced G2-PCC assay as a biodosimetry triage tool for assessing a wide range of low and acute high radiation dose exposures of photons. Towards this initiative, chromosome aberrations induced by low and high doses of x-rays were evaluated and characterized in G2-prematurely condensed chromosomes (G2-PCCs) by fluorescence in situ hybridization (FISH) using human centromere and telomere specific PNA (peptide nucleic acid) probes. A dose dependent increase in the frequency of dicentric chromosomes was observed in the G2-PCCs up to 20 Gy of x-rays. The combined yields of dicentrics and rings in the G2-PCCs showed a clear dose dependency up to 20 Gy from 0.02/cell for 0.1 Gy to 14.98/cell for 20 Gy. Centric rings were observed more frequently than acentric ring chromosomes in the G2-PCCs at all the radiation doses from 1 Gy to 20 Gy. A head-to-head comparison was also performed by FISH on the yields of chromosome aberrations induced by different doses of x-rays (0 Gy -7.5 Gy) in colcemid arrested metaphase chromosomes and calyculin A induced G2-PCCs. In general, the frequencies of dicentrics, rings and acentric fragments were slightly higher in G2-PCCs than in colcemid arrested metaphase chromosomes at all the radiation doses, but the differences were not statistically significant. To reduce the turnaround time for absorbed radiation dose estimation, attempt was made to obtain G2-PCCs by reducing the culture time to 36 hrs. The absorbed doses estimated in x-rays irradiated (0,1,2 and 4 Gy) G2-PCCs after 36 hrs of culture were grossly like that of G2-PCCs and colcemid arrested metaphase chromosomes prepared after 48 hrs of culture. Our study indicates that the shortened version of calyculin A induced G2-PCC assay coupled with the FISH staining technique can serve as an effective triage biodosimetry tool for large-scale radiological/nuclear incidents.

Science & Technology - Other Topics↗

High and low dose radiation effects on mammary adenocarcinoma cells – an epigenetic connection

The successful treatment of cancer, including breast cancer, depends largely on radiation therapy and proper diagnostics. The effect of ionizing radiation on cells and tissues depends on the radiation dose and energy level, but there is insufficient evidence concerning how tumor cells respond to the low and high doses of radiation that are often used in medical diagnostic and treatment modalities. The purpose of this study was to investigate radiation-induced gene expression changes in the MCF7 breast adenocarcinoma cell line. Using microarray technology tools, we were able to screen the differential gene expressions profiles between various radiation doses applied to MCF-7 cells. Here, we report the substantial alteration in the expression level of genes after high-dose treatment. In contrast, no dramatic gene expression alterations were noticed after the application of low and medium doses of radiation. In response to a high radiation dose, MCF-7 cells exhibited down-regulation of biological pathways such as cell cycle, DNA replication, and DNA repair and activation of the p53 pathway. Similar dose-dependent responses were seen on the epigenetic level, which was tested by a microRNA expression analysis. MicroRNA analysis showed dose-dependent radiation-induced microRNA expression alterations that were associated with cell cycle arrest and cell death. An increased rate of apoptosis was determined by an Annexin V assay. The results of this study showed that high doses of radiation affect gene expression genetically and epigenetically, leading to alterations in cell cycle, DNA replication, and apoptosis.

59 BASIC BIOLOGICAL SCIENCES↗

Post-Remediation Radiological Dose Assessment, Painesville Site, Painesville, Ohio

A post-remediation radiological dose assessment was conducted for the Formerly Utilized Sites Remedial Action Program (FUSRAP) Painesville Site by using the measured residual concentrations of the radionuclides of concern following the completion of remedial action. The site’s FUSRAP-related constituents of concern (COCs) are radionuclides associated with past activities conducted by the Manhattan Engineer District (MED) and Atomic Energy Commission (AEC) in support of the Nation’s early atomic energy and weapons program, and include radium-226 (Ra-226), thorium-230 (Th-230), thorium-232 (Th-232), and total uranium (Total U). Remedial actions were conducted at the site in accordance with the Final Record of Decision for the Painesville Site, Painesville, Ohio (ROD) (USACE 2006). In the ROD, the U.S. Army Corps of Engineers (USACE) determined that the U.S. Nuclear Regulatory Commission (NRC) standards for decommissioning of licensed facilities found in Title 10, Part 20.1402 of the Code of Federal Regulations (10 CFR 20.1402) and in the Ohio Administrative Code (OAC) 3701:1-38-22(B) are applicable or relevant and appropriate requirements (ARARs) for the site. On the basis of the ARAR analysis, a total effective dose equivalent (TEDE) goal of 25 millirem per year (mrem/yr) was assumed for the site with a construction worker considered as the average member of the critical group. Derived concentration guideline levels (DCGLs) for residual radioactivity of the COCs in soil were developed for the Painesville Site using the RESRAD (Version 6.22) computer code (Yu et al. 2001), which was designed to estimate radiation doses and risks from RESidual RADioactive materials. The DCGLs represent activity levels above site average background activity corresponding to the 25-mrem/yr criterion for a construction worker scenario. The DCGLs are above the background activity concentrations and represent average concentration guidelines. The DCGLs and average background activity concentrations are provided in Table 1. The Final Feasibility Study Addendum (USACE 2005) provides a complete description of the derivation of the DCGLs for the Painesville Site. A post-remediation radiological dose assessment was performed to determine the potential radiation doses to a construction worker, consistent with the approach used to develop the DCGLs for the Painesville Site given in the Final Feasibility Study Addendum (USACE 2005) and ROD (USACE 2006). A second more conservative dose assessment was performed to determine the potential radiation doses to an urban resident who is assumed to live and garden on the site. To further evaluate the long-term protectiveness of the remedial action, a third dose assessment was conducted to determine the potential radiation doses to a hypothetical subsistence farmer. The primary difference between exposure to an urban resident versus a conservative subsistence farmer would be an increase in the amount of foodstuffs (homegrown produce, milk, and beef) produced/cultivated and consumed on-site.

54 ENVIRONMENTAL SCIENCES↗

Increasing the Dose Rate on the DARHT-II Accelerator

Recent studies have shown a strong correlation between spot size on target and the dose. At higher doses, the spot size is larger. At very low doses (< 75 R @ 1m per pulse) all four spots are small and essentially the same with 50%MTFs of 1.0-1.2 mm. For higher dose pulse formats, the first two pulses, P1 and P2 remain small (< 1.2 mm 50%MTF) and relatively independent of dose. The later pulses, P3 and P4, become larger as the dose increases. Longer pulse lengths are required to achieve higher doses. There are simulations that suggest space charge neutralization and current neutralization could be introducing dynamic changes in the spot size over the pulse. This implies that increasing the dose rate will allow for reduced pulse lengths and spot size for the same dose.

43 PARTICLE ACCELERATORS↗

Absorbed dose measurements and predictions on LDEF

The overall radiation environment of the Long Duration Exposure Facility (LDEF) was determined in part through the use of thermoluminescent detectors (TLD's) which were included in several experiments. The results given are from four experiments (A0015 Biostack, M0004 Fiber Optics Data Link, P0004 Seeds in Space, and P0006 Linear Energy Transfer Spectrum Measurement) and represent a large fraction of existing absorbed dose data. The TLD's were located on the leading and the trailing edges and the Earth end of the spacecraft under various shielding depths (0.48 to 15.4 g/sq cm). The measured absorbed doses were found to reflect both directional dependence of incident trapped protons and shielding. At the leading edge, doses ranged from 2.10 to 2.58 Gy under shielding of 2.90 to 1.37 g/sq cm Al equivalent (M0004). At the trailing edge, doses varied from 3.04 to 4.49 Gy under shielding of 11.7 to 3.85 g/sq cm (A0015), doses varied from 2.91 to 6.64 Gy under shielding of 11.1 to 0.48 g/sq cm (P0004), and a dose range of 2.66 to 6.48 Gy was measured under shielding of 15.4 to 0.48 g/sq cm (P0006). At the Earth end of the spacecraft, doses from 2.41 to 3.93 Gy were found under shielding of 10.0 to 1.66 g/sq cm (A0015). The effect of the trapped proton anisotropy was such that the western side of LDEF received more than 2 times the dose of the eastern side at shielding depths of approximately 1 g/sq cm. Calculations utilizing a directional model of trapped proton spectra predict smaller doses than those measured, being about 50 percent of measured values at the trailing edge and Earth end, and about 80 percent near the leading edge.

Frank, A. L.↗

Absorbed dose measurements on LDEF and comparisons with predictions

The radiation environment on LDEF was monitored by cumulative absorbed dose measurements made with TLDs at different locations and shielding depths. The TLDs were included in four experiments: A0015(a) Biostack, P0004 Seeds in Space and P0006 Linear Energy Transfer Spectrum Measurements at the trailing edge (west side) of the satellite; M0004 Fiber Optics Data Link at the leading edge (east side); and A0015(b) Biostack at the Earth side. The shielding depths varied between 0.48 and 15.4 g/cm2, Al equivalent. Both the directional dependence of trapped protons incident on the satellite and the shielding thickness were reflected in absorbed dose values. The trapped proton anisotropy was measured by TLDs at the east and west sides of LDEF. At the east side doses ranged from 2.10 to 2.58 Gy under shielding of 2.90 to 1.37 g/cm2 (M0004) while on the west side doses ranged from 2.66 to 6.48 Gy under shielding of 15.4 to 0.48 g/cm2 (P0006). The west side doses were more than a factor of two higher, where the vertical shielding thicknesses to space were equal. Other west side doses of 3.04 to 4.49 Gy under shielding of 11.7 to 3.85 g/cm2 (A0015(a)) and 2.91 to 6.64 Gy under shielding of 11.1 to 0.48 g/cm2 (P0004) generally agreed with the P0006 results. The Earth side doses of 2.41 to 3.93 Gy under shielding of 10.0 to 1.66 g cm2 (A0015(b)) were intermediate between the east side and west side doses. Calculations utilizing a model of trapped proton spectra were performed by Watts et al. (1993) and comparisons of dose measurement and calculations may be found in a companion paper (Armstrong et al., 1996).

Flight Experiment↗

Estimation Of Organ Doses From Solar Particle Events For Future Space Exploration Missions

Radiation protection practices define the effective dose as a weighted sum of equivalent dose over major organ sites for radiation cancer risks. Since a crew personnel dosimeter does not make direct measurement of the effective dose, it has been estimated with skin-dose measurements and radiation transport codes for ISS and STS missions. If sufficient protection is not provided near solar maximum, the radiation risk can be significant due to exposure to sporadic solar particle events (SPEs) as well as to the continuous galactic cosmic radiation (GCR) on future exploratory-class and long-duration missions. For accurate estimates of overall fatal cancer risks from SPEs, the specific doses at various blood forming organs (BFOs) were considered, because proton fluences and doses vary considerably across marrow regions. Previous estimates of BFO doses from SPEs have used an average body-shielding distribution for the bone marrow based on the computerized anatomical man model (CAM). With the development of an 82-point body-shielding distribution at BFOs, the mean and variance of SPE doses in the major active marrow regions (head and neck, chest, abdomen, pelvis and thighs) will be presented. Consideration of the detailed distribution of bone marrow sites is one of many requirements to improve the estimation of effective doses for radiation cancer risks.

Kim, Myung-Hee↗

Can the Equivalent Sphere Model Approximate Organ Doses in Space Radiation Environments?

In space radiation calculations it is often useful to calculate the dose or dose equivalent in blood-forming organs (BFO). the skin or the eye. It has been customary to use a 5cm equivalent sphere to approximate the BFO dose. However previous studies have shown that a 5cm sphere gives conservative dose values for BFO. In this study we use a deterministic radiation transport with the Computerized Anatomical Man model to investigate whether the equivalent sphere model can approximate organ doses in space radiation environments. We find that for galactic cosmic rays environments the equivalent sphere model with an organ-specific constant radius parameter works well for the BFO dose equivalent and marginally well for the BFO dose and the dose equivalent of the eye or the skin. For solar particle events the radius parameters for the organ dose equivalent increase with the shielding thickness, and the model works marginally for BFO but is unacceptable for the eye or the skin The ranges of the radius parameters are also shown and the BFO radius parameters are found to be significantly larger than 5 cm in all eases.

Zi-Wei, Lin↗

Depth Dose Distribution Study within a Phantom Torso after Irradiation with a Simulated Solar Particle Event at NSRL

The adequate knowledge of the radiation environment and the doses incurred during a space mission is essential for estimating an astronaut's health risk. The space radiation environment is complex and variable, and exposures inside the spacecraft and the astronaut's body are compounded by the interactions of the primary particles with the atoms of the structural materials and with the body itself Astronauts' radiation exposures are measured by means of personal dosimetry, but there remains substantial uncertainty associated with the computational extrapolation of skin dose to organ dose, which can lead to over- or underestimation of the health risk. Comparisons of models to data showed that the astronaut's Effective dose (E) can be predicted to within about a +10% accuracy using space radiation transport models for galactic cosmic rays (GCR) and trapped radiation behind shielding. However for solar particle event (SPE) with steep energy spectra and for extra-vehicular activities on the surface of the moon where only tissue shielding is present, transport models predict that there are large differences in model assumptions in projecting organ doses. Therefore experimental verification of SPE induced organ doses may be crucial for the design of lunar missions. In the research experiment "Depth dose distribution study within a phantom torso" at the NASA Space Radiation Laboratory (NSRL) at BNL, Brookhaven, USA the large 1972 SPE spectrum was simulated using seven different proton energies from 50 up to 450 MeV. A phantom torso constructed of natural bones and realistic distributions of human tissue equivalent materials, which is comparable to the torso of the MATROSHKA phantom currently on the ISS, was equipped with a comprehensive set of thermoluminescence detectors and human cells. The detectors are applied to assess the depth dose distribution and radiation transport codes (e.g. GEANT4) are used to assess the radiation field and interactions of the radiation field with the phantom torso. Lymphocyte cells are strategically embedded at selected locations at the skin and internal organs and are processed after irradiation to assess the effects of shielding on the yield of chromosome damage. The initial focus of the present experiment is to correlate biological results with physical dosimetry measurements in the phantom torso. Further on, the results of the passive dosimetry within the anthropomorphic phantoms represent the best tool to generate reliable data to benchmark computational radiation transport models in a radiation field of interest. The presentation will give first results of the physical dose distribution, the comparison with GEANT4 computer simulations based on a Voxel model of the phantom, and a comparison with the data from the chromosome aberration study.

Berger, Thomas↗

Verification of Calculated Skin Doses in Postmastectomy Helical Tomotherapy

Purpose: To verify the accuracy of calculated skin doses in helical tomotherapy for postmastectomy radiation therapy (PMRT). Methods and Materials: In vivo thermoluminescent dosimeters (TLDs) were used to measure the skin dose at multiple points in each of 14 patients throughout the course of treatment on a TomoTherapy Hi.Art II system, for a total of 420 TLD measurements. Five patients were evaluated near the location of the mastectomy scar, whereas 9 patients were evaluated throughout the treatment volume. The measured dose at each location was compared with calculations from the treatment planning system. Results: The mean difference and standard error of the mean difference between measurement and calculation for the scar measurements was -1.8% {+-} 0.2% (standard deviation [SD], 4.3%; range, -11.1% to 10.6%). The mean difference and standard error of the mean difference between measurement and calculation for measurements throughout the treatment volume was -3.0% {+-} 0.4% (SD, 4.7%; range, -18.4% to 12.6%). The mean difference and standard error of the mean difference between measurement and calculation for all measurements was -2.1% {+-} 0.2% (standard deviation, 4.5%: range, -18.4% to 12.6%). The mean difference between measured and calculated TLD doses was statistically significant at two standard deviations of the mean, but was not clinically significant (i.e., was <5%). However, 23% of the measured TLD doses differed from the calculated TLD doses by more than 5%. Conclusions: The mean of the measured TLD doses agreed with TomoTherapy calculated TLD doses within our clinical criterion of 5%.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Association Between Maximal Skin Dose and Breast Brachytherapy Outcome: A Proposal for More Rigorous Dosimetric Constraints

Purpose: Multiple investigations have used the skin distance as a surrogate for the skin dose and have shown that distances <6 mm have been associated with late toxicity after MammoSite brachytherapy. No publications have yet described the relationship between the actual maximal skin dose and the outcome. The present study analyzed the maximal skin dose delivered and the occurrence of late toxicity in a large cohort of patients with prolonged follow-up. Methods: A total of 96 patients treated with breast brachytherapy between 2000 and 2007 for whom complete planning and follow-up data were available were included in the present analysis. The median follow-up was 48 months (range, 24-111). Of the 96 patients, 40 were treated with multicatheter interstitial brachytherapy and 56 with MammoSite. A multivariate statistical analysis was performed to determine the relationship between several dosimetric parameters and patient outcome. Results: The treatment was well tolerated, with 98% of patients experiencing good to excellent cosmesis. Significant late toxicity was uncommon. The maximal dose delivered to the skin was significantly associated with the incidence of any degree of telangiectasia (p = .009) and moderate to severe fibrosis (p = .010). The incidence of late toxicity was significantly increased when the dose to the skin was >4.05 Gy/fraction. Conclusion: The initial skin dose recommendations have been based on safe use and the avoidance of significant toxicity. The results from the present study have suggested that patients might further benefit if more rigorous constraints were applied and if the skin dose were limited to 120% of the prescription dose.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Radiotherapy Doses of 80 Gy and Higher Are Associated With Lower Mortality in Men With Gleason Score 8 to 10 Prostate Cancer

Purpose: Men with Gleason score (GS) 8-10 prostate cancer (PCa) are assumed to have a high risk of micrometastatic disease at presentation. However, local failure is also a major problem. We sought to establish the importance of more aggressive local radiotherapy (RT) to {>=}80 Gy. Methods and Materials: There were 226 men treated consecutively with RT {+-} ADT from 1988 to 2002 for GS 8-10 PCa. Conventional, three-dimensional conformal or intensity-modulated (IM) RT was used. Radiation dose was divided into three groups: (1) <75 Gy (n = 50); (2) 75-79.9 Gy (n = 60); or (3) {>=}80 Gy (n = 116). The endpoints examined included biochemical failure (BF; nadir + 2 definition), distant metastasis (DM), cause-specific mortality, and overall mortality (OM). Results: Median follow-up was 66, 71, and 58 months for Groups 1, 2, and 3. On Fine and Gray's competing risk regression analysis, significant predictors of reduced BF were RT dose {>=}80 Gy (p = 0.011) and androgen deprivation therapy duration {>=}24 months (p = 0.033). In a similar model of DM, only RT dose {>=}80 Gy was significant (p = 0.007). On Cox regression analysis, significant predictors of reduced OM were RT dose {>=}80 Gy (p = 0.035) and T category (T3/4 vs. T1, p = 0.041). Dose was not a significant determinant of cause-specific mortality. Results for RT dose were similar in a model with RT dose and ADT duration as continuous variables. Conclusion: The results indicate that RT dose escalation to {>=}80 Gy is associated with lower risks of BF, DM, and OM in men with GS 8-10 PCa, independently of androgen deprivation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗