Development and validation of a GEANT4 radiation transport code for CT dosimetry.

The authors have created a radiation transport code using the GEANT4 Monte Carlo toolkit to simulate pediatric patients undergoing CT examinations. The focus of this paper is to validate their simulation with real-world physical dosimetry measurements using two independent techniques. Exposure measurements were made with a standard 100-mm CT pencil ionization chamber, and absorbed doses were also measured using optically stimulated luminescent (OSL) dosimeters. Measurements were made in air with a standard 16-cm acrylic head phantom and with a standard 32-cm acrylic body phantom. Physical dose measurements determined from the ionization chamber in air for 100 and 120 kVp beam energies were used to derive photon-fluence calibration factors. Both ion chamber and OSL measurement results provide useful comparisons in the validation of the Monte Carlo simulations. It was found that simulated and measured CTDI values were within an overall average of 6% of each other.

Comparison of measured and calculated dose rates near nuclear medicine patients.

Widely used release criteria for patients receiving radiopharmaceuticals (NUREG-1556, Vol. 9, Rev.1, Appendix U) are known to be overly conservative. The authors measured external exposure rates near patients treated with I, Tc, and F and compared the measurements to calculated values using point and line source models. The external exposure dose rates for 231, 11, and 52 patients scanned or treated with I, Tc, and F, respectively, were measured at 0.3 m and 1.0 m shortly after radiopharmaceutical administration. Calculated values were always higher than measured values and suggested the application of "self-shielding factors," as suggested by Siegel et al. in 2002. The self-shielding factors of point and line source models for I at 1 m were 0.60 ± 0.16 and 0.73 ± 0.20, respectively. For Tc patients, the self-shielding factors for point and line source models were 0.44 ± 0.19 and 0.55 ± 0.23, and the values were 0.50 ± 0.09 and 0.60 ± 0.12, respectively, for F (all FDG) patients. Treating patients as unshielded point sources of radiation is clearly inappropriate. In reality, they are volume sources, but treatment of their exposures using a line source model with appropriate self-shielding factors produces a more realistic, but still conservative, approach for managing patient release.

Realistic reference adult and paediatric phantom series for internal and external dosimetry.

A new generation of realistic, image-based anthropomorphic phantoms has been developed based on the reference masses and organ definitions given in the International Commission on Radiological Protection Publication 89. Specific absorbed fractions for internal radiation sources have been calculated for photon and electron sources for many body organs. Values are similar to those from the previous generation of 'stylized' (mathematical equation-based) models, but some differences are seen, particularly at low particle or photon energies, due to the more realistic organ geometries, with organs generally being closer together, and with some touching and overlapping. Extension of this work, to use these phantoms in Monte Carlo radiation transport simulation codes with external radiation sources, is an important area of investigation that should be undertaken.

Image quantification for radiation dose calculations--limitations and uncertainties.

Radiation dose calculations in nuclear medicine depend on quantification of activity via planar and/or tomographic imaging methods. However, both methods have inherent limitations, and the accuracy of activity estimates varies with object size, background levels, and other variables. The goal of this study was to evaluate the limitations of quantitative imaging with planar and single photon emission computed tomography (SPECT) approaches, with a focus on activity quantification for use in calculating absorbed dose estimates for normal organs and tumors. To do this we studied a series of phantoms of varying complexity of geometry, with three radionuclides whose decay schemes varied from simple to complex. Four aqueous concentrations of 99mTc, ¹³¹I, and ¹¹¹In (74, 185, 370, and 740 kBq mL⁻¹) were placed in spheres of four different sizes in a water-filled phantom, with three different levels of activity in the surrounding water. Planar and SPECT images of the phantoms were obtained on a modern SPECT/computed tomography (CT) system. These radionuclides and concentration/background studies were repeated using a cardiac phantom and a modified torso phantom with liver and "tumor" regions containing the radionuclide concentrations and with the same varying background levels. Planar quantification was performed using the geometric mean approach, with attenuation correction (AC), and with and without scatter corrections (SC and NSC). SPECT images were reconstructed using attenuation maps (AM) for AC; scatter windows were used to perform SC during image reconstruction. For spherical sources with corrected data, good accuracy was observed (generally within ±10% of known values) for the largest sphere (11.5 mL) and for both planar and SPECT methods with 99mTc and ¹³¹I, but were poorest and deviated from known values for smaller objects, most notably for ¹¹¹In. SPECT quantification was affected by the partial volume effect in smaller objects and generally showed larger errors than the planar results in these cases for all radionuclides. For the cardiac phantom, results were the most accurate of all of the experiments for all radionuclides. Background subtraction was an important factor influencing these results. The contribution of scattered photons was important in quantification with ¹³¹I; if scatter was not accounted for, activity tended to be overestimated using planar quantification methods. For the torso phantom experiments, results show a clear underestimation of activity when compared to previous experiment with spherical sources for all radionuclides. Despite some variations that were observed as the level of background increased, the SPECT results were more consistent across different activity concentrations. Planar or SPECT quantification on state-of-the-art gamma cameras with appropriate quantitative processing can provide accuracies of better than 10% for large objects and modest target-to-background concentrations; however when smaller objects are used, in the presence of higher background, and for nuclides with more complex decay schemes, SPECT quantification methods generally produce better results.

Influence of total-body mass on the scaling of S-factors for patient-specific, blood-based red-marrow dosimetry.

To perform patient-specific, blood-based red-marrow dosimetry, dose conversion factors (the S factors in the MIRD formalism) have to be scaled by patients' organ masses. The dose to red marrow includes both self-dose and cross-irradiation contributions. Linear mass scaling for the self-irradiation term only is usually applied as a first approximation, whereas the cross-irradiation term is considered to be mass independent. Recently, the need of a mass scaling correction on both terms, not necessarily linear and dependent on the radionuclide, has been highlighted in the literature. S-factors taking into account different mass adjustments of organs are available in the OLINDA/EXM code. In this paper, a general algorithm able to fit the mass-dependent factors S(rm<--tb) and S(rm<--rm) is suggested and included in a more general equation for red-marrow dose calculation. Moreover, parameters to be considered specifically for therapeutic radionuclides such as (131)I, (90)Y and 177Lu are reported. The red-marrow doses calculated by the traditional and new algorithms are compared for (131)I in ablation therapy (14 pts), 177Lu- (13 pts) and (90)Y- (11 pts) peptide therapy for neuroendocrine tumours, and (90)Y-Zevalin therapy for NHL (21 pts). The range of differences observed is as follows: -36% to -10% for (131)I ablation, -22% to 5% for 177Lu-DOTATATE, -9% to 11% for (90)Y-DOTATOC and -8% to 6% for (90)Y-Zevalin. All differences are mostly due to the activity in the remainder of the body contributing to cross-irradiation. This paper quantifies the influence of mass scaling adjustment on usually applied therapies and shows how to derive the appropriate parameters for other radionuclides and radiopharmaceuticals.

Specific absorbed fractions for internal photon emitters calculated for a tomographic model of a pregnant woman.

Specific absorbed fractions are essential for calculation of radiation dose from internal emitters. Existing specific absorbed fractions for pregnant women were calculated using the stylized models; in this work, a partial-body tomographic model for a pregnant woman was constructed from a rare set of CT images. Based on this tomographic model, the Monte Carlo code, EGS4-VLSI, was used to derive specific absorbed fractions. Monoenergetic, isotropic photon emitters from 15 keV to 4 MeV were distributed in different source organs, and doses were calculated to many target regions in the body. Even though the results showed general agreement with previous studies for higher energies, significant differences were also found, especially for lower energies. The main reasons for the differences are due to the variation of mass, geometry, and organ distances, and they demonstrate the influence of more realistic body models on dose calculations.

Developments in the internal dosimetry of radiopharmaceuticals.

Various radionuclides are used in nuclear medicine in different diagnostic and therapeutic procedures. Recently, interest has grown in therapeutic agents for some interesting applications in nuclear medicine. Internal dose models and methods in use for many years are well established, and can give radiation doses to stylised models representing reference individuals. Kinetic analyses need to be carefully planned, and dose conversion factors that are most similar to the subject in question should be chosen, which can then be tailored somewhat to be more patient-specific. Internal dose calculations, however, are currently not relevant in patient management in internal emitter therapy, as they are not sufficiently accurate or detailed to guide clinical decision-making, and as calculated doses have historically not been well correlated with observed effects on tissues. Great strides are being made at many centres regarding the use of patient image data to construct individualised voxel-based models for more detailed and patient-specific dose calculations, and new findings are encouraging regarding improvement of internal dose models to provide better correlations of dose and effect. These recent advances make it likely that the relevance will soon change to be more similar to that of external beam treatment planning.

Evolution and status of bone and marrow dose models.

Investigations at the University of Leeds under the direction of F.W. Spiers in the early 1960s through the late 1970s established the first comprehensive assessment of marrow dose conversion factors (DCFs) for beta-emitting radionuclides within the volume or on the surface of trabecular bone. These DCFs were subsequently used in deriving radionuclide S values for skeletal tissues published in MIRD Pamphlet No. 11. Eckerman re-evaluated this work and extended the methods of Spiers to radionuclides within the marrow to provide DCFs for fifteen skeletal regions in computational models representing individuals of six different ages. These results were used in the MIRDOSE3 software. Bouchet et al. used updated information on regional bone and marrow masses, as well as 3D electron transport techniques, to derive radionuclide S values in skeletal regions of the adult. Although these two efforts are similar in most regards, the models differ in three respects in: (1) the definition of the red marrow region, (2) the definition of a surface source of activity, and (3) the assumption applied in transporting electrons through the trabecular endosteum. In this study, a review of chord-based skeletal models is given, followed by a description of the differences in the Eckerman and Bouchet et al. transport models. Finally, new data from NMR microscopy and radiation transport in trabecular bone is applied to address item (1) above. Dose conversion factors from MIRD 11, the Eckerman model, the Bouchet et al. model, and a revised model are compared for several radionuclides important to internal emitter therapy.

A voxel-based head-and-neck phantom built from tomographic colored images.

Recent progress in computer speed and medical imaging has made possible the development of a new family of anthropomorphic models, based on a volume elements (voxels) approach to phantom design. Such phantoms can represent details of the anatomical structures of the human body more realistically. Tomographic images (CT or MRI) contain the basic information for the construction of voxel-based phantoms. Use of voxel-based phantoms has its most significant application in the planning of individual patients therapy. To be implemented, results must be obtained in a reasonably short period of time. The segmentation of organs and tissues is a critical step in this process. This article presents a new approach in the construction of voxel-based phantoms that was implemented to simplify the segmentation process of organs and tissues, reducing the time used in this procedure. A voxel-based head and neck phantom, called MCvoxEL, was built using this new approach. The volumes and masses of the segmented organs and tissues were compared with data published by other investigators.

A theoretical model for prescription of the patient-specific therapeutic activity for radioiodine therapy of Graves' disease.

A fundamental function of the thyroid is to extract iodine from the blood, synthesize it into thyroid hormones, and release it into the circulation under feedback control by pituitary-secreted hormones. This capability of the thyroid, termed as functionality, can in principle be related to the severity of hyperthyroidism in individual patients. In this paper the uptake and release of 131I by the thyroid following the administration of 131I therapy for Graves' disease has been theoretically studied. The kinetics of iodine in the thyroid and blood have been evaluated using a two-compartment model. This simplified model appears to be adequate for dosimetry purposes and allows one to correlate levels of increased thyroid functionality (hyperthyroidism) with clinically measurable kinetic parameters. An expression has been derived for the rate of change of thyroid mass following therapy; this has the same form as an empirical relationship described in an earlier work. A method is presented for calculation of the amount of radioiodine activity to be administered to individual patients in order to achieve the desired final functionality of the gland. The activity to be administered is based on measurements of 131I kinetics after the administration of a 'low-activity' (1850 kBq) tracer for treatment planning.

Vascular-targeted radioimmunotherapy with the alpha-particle emitter 211At.

Astatine-211, an alpha-particle emitter, was employed in a model system for vascular-targeted radioimmunotherapy of small tumors in mouse lung to compare its performance relative to other radioisotopes in the same system. Astatine-211 was coupled to the lung blood vessel-targeting monoclonal antibody 201B with N-succinimidyl N-(4-[211At]astatophenethyl) succinamate linker. Biodistribution data showed that the conjugate delivered 211At to the lung (260-418% ID/g), where it remained with a biological half-time of about 30 h. BALB/c mice bearing about 100 lung tumor colonies of EMT-6 cells, each about 2000 cells in size, were treated with 211At-labeled monoclonal antibody 201B. The administered activity of 185 kBq per animal extended the life span of treated mice over untreated controls. Injections of 370 kBq, corresponding to an absorbed dose of 25-40 Gy, were necessary to eradicate all of the lung tumors. Mice receiving 740 kBq of 211At-labeled monoclonal antibody 201B developed pulmonary fibrosis 3-4 months after treatment, as did mice treated with 3700 kBq of the alpha-particle emitter 213Bi-labeled monoclonal antibody 201B in previous work. Animals that were injected with 211At bound to untargeted IgG or to glycine, as control agents, also demonstrated therapeutic effects relative to untreated controls. Control groups that received untargeted 211At required about twice as much administered activity for effective therapy as did groups with lung-targeted radioisotope. These results were not consistent with radioisotope biodistribution and dosimetry calculations that indicated that lung-targeted 211At should be at least 10-fold more efficient for lung colony therapy than 211At bound to nontargeting controls. The data showed that 211At is useful for vascular-targeted radioimmunotherapy because lung tumor colonies were eradicated in the mice. Work in this model system demonstrates that vascular targeting of alpha-particle emitters is an efficient therapy for small perivascular tumors and may be applicable to human disease when specific targeting agents are identified.

Photon specific absorbed fractions calculated in the trunk of an adult male voxel-based phantom.

A new approach for calculating internal dose estimates was developed through the use of a more realistic computational model of the human body. The study demonstrates the capability of building a patient-specific phantom with voxel-based data for the simulation of radiation transport and energy deposition using Monte Carlo methods such as the MCNP-4B code. MCNP-4B was used to calculate absorbed fractions for photons in a voxel-based phantom, and values were compared to reference values from traditional phantoms used for many years. Results obtained in general agreed well with previous values, but considerable differences were found in some cases due to two major causes; differences in the organ masses between the phantoms and the occurrence of organ overlap in the voxel-based phantom (which is not well modeled in the mathematical phantoms). These new techniques offer promise of developing a new generation of more realistic phantoms for internal, as well as external, dose assessment. The principal area of implementation in internal dose assessment should be the development of patient-specific dose estimates in nuclear medicine therapy, such as radioimmunotherapy (RIT). However, as new voxel-based phantoms for different individuals can be developed, they may also be used with the techniques developed here to derive new absorbed fractions and replace the traditional values usedfor other applications in internal and external dose assessment, which have been based on mathematical constructs that are not always very representative of real human organs.

Study of the correlation between administered activity and radiation committed dose to the thyroid in 131I therapy of Graves' disease.

Substantial reduction in the thyroid volume (up to 70-80%) after 131I therapy of Graves' disease has been demonstrated and reported in the literature. Recently a mathematical model of thyroid mass reduction during the first month after therapy has been developed and a new algorithm for the radiation committed dose calculation has been proposed. Reduction of the thyroid mass and the radiation committed dose to the gland depend on a parameter k, defined for each subject. The calculation of k allows the prediction of the activity to administer, depending on the radiation committed dose chosen by the physician. In this paper a method for calculating k is proposed. The calculated values of k are compared to values derived from measurements of the changes in thyroid mass in twenty-six patients treated by 131I for Graves' disease. The radiation committed dose to the thyroid can be predicted within 21%, and the radioiodine activity to administer to the patient can be predicted within 22% using the calculated values of k. The thyroid volume reduction during the first month after therapy administration can be also predicted with good accuracy using the calculated values of k. The radiation committed dose and the radioiodine activity to administer were calculated using a new, very simple algorithm. A comparison between the values calculated by this new algorithm and the old, classical Marinelli-Quimby algorithm shows that the new method is more accurate.

Pattern of uptake and excretion of (18)F-FDG in the lactating breast.

UNLABELLED: Excretion of radiopharmaceuticals into breast milk poses a potential risk to infants and clear recommendations regarding interruption times are required. There are few data available regarding the impact of (18)F-FDG on this issue. With increasing use of PET for oncologic imaging and its potential advantages to nursing mothers because of its short physical half-life compared with other commonly used tumor imaging agents such as (67)Ga and (201)Tl, evaluation of the excretion pattern of this agent in breast milk is important. METHODS: We have evaluated the uptake of FDG in the breasts in 7 women, 6 of whom were lactating and 1 of whom was in early postpartum but had not commenced breast-feeding. Milk samples were obtained from 4 of the lactating women, including serial samples from 1. RESULTS: Significantly increased breast uptake was identified in all lactating breasts but not in 1 breast consistently refused by the nursing infant or in the woman who had not begun breast-feeding after delivery of her child. No qualitative change or semiquantitative estimate of radiotracer uptake in the breast was seen after expression of breast milk. Decay-corrected activity measurable in breast milk ranged from 5.54 to 19.3 Bq/mL/MBq injected. Using a standard model of breast-feeding, the calculated maximum cumulative dose to the infant, 0.085 mSv with no interruption of breast-feeding, is well below the recommended limit of 1 mSv. CONCLUSION: High uptake of FDG in the lactating breast appears to be related to suckling. There is, however, little secretion of activity into breast milk. Accordingly, a higher radiation dose is received by the infant from close contact with the breast than from ingestion of radioactive milk.

Modeling radiation dose and effects from internal emitters in nuclear medicine: from the whole body to individual cells.

In nuclear medicine, proper application of radiation protection principles depends on balancing the potential risks of exposure to ionizing radiation against its possible benefits. Average doses to organs, in diagnostic or therapeutic applications, are not always representative of the doses received at the tissue or cellular level. Therefore, understanding of the relationship between the overall biological effect and absorbed dose delivered by the radiopharmaceutical may require study of doses at the organ, tissue, or cell level. In this paper, we review current models for radiation dose assessment, with consideration of the different models and assumptions employed for study at all levels of investigation.

Contribution to red marrow absorbed dose from total body activity: a correction to the MIRD method.

UNLABELLED: The contribution to red marrow absorbed dose from beta-emitting radionuclides distributed uniformly in the total body can be overestimated using either MIRD 11 or MIRDOSE3. The S value assigned to the red marrow target region from activity distributed in the remainder of the body is of particular concern. The assumption that the specific absorbed fraction for total body irradiating red marrow and other skeletal tissues is the inverse of the total-body mass can result in an inappropriate remainder-of-body contribution to marrow dose. We evaluated differences in the calculation of marrow dose using MIRD 11 and MIRDOSE3 formulations and developed methods to correct the results from either to remove inappropriate contributions. When bone takes up significantly less activity than is predicted from an apportionment of remainder-tissue activity based on mass, the standard remainder-of-body correction may substantially overestimate the electron component of the S value from remainder tissues to red marrow using either MIRD 11 or MIRDOSE3. If bone takes up activity, this contribution is negligible using MIRD 11 S values but remains with MIRDOSE3 S values. This overestimate can be significant, particularly when the residence time of activity in the remainder of the body is much higher than in the red marrow and a different correction is needed. As the ratio of the remainder of body to marrow residence time is lowered, the overestimate becomes less significant. CONCLUSION: In this article, we show the magnitude of this overestimate (which is most important for nuclides with large "nonpenetrating" emission components and for pharmaceuticals that have a large ratio of remainder of body to marrow residence times), show the appropriate corrections to be made in each case, and propose a new method for calculating marrow dose contributions that will avoid this complication in future applications. Because all models give approximate doses for real patients, with uncertainties within those involved in these corrections, we do not suggest that changes be made to existing marrow dose estimates. We suggest only that future calculations be as accurate as possible.

Monte Carlo MCNP-4B-based absorbed dose distribution estimates for patient-specific dosimetry.

UNLABELLED: This study was intended to verify the capability of the Monte Carlo MCNP-4B code to evaluate spatial dose distribution based on information gathered from CT or SPECT. METHODS: A new three-dimensional (3D) dose calculation approach for internal emitter use in radioimmunotherapy (RIT) was developed using the Monte Carlo MCNP-4B code as the photon and electron transport engine. It was shown that the MCNP-4B computer code can be used with voxel-based anatomic and physiologic data to provide 3D dose distributions. RESULTS: This study showed that the MCNP-4B code can be used to develop a treatment planning system that will provide such information in a time manner, if dose reporting is suitably optimized. If each organ is divided into small regions where the average energy deposition is calculated with a typical volume of 0.4 cm(3), regional dose distributions can be provided with reasonable central processing unit times (on the order of 12-24 h on a 200-MHz personal computer or modest workstation). Further efforts to provide semiautomated region identification (segmentation) and improvement of marrow dose calculations are needed to supply a complete system for RIT. It is envisioned that all such efforts will continue to develop and that internal dose calculations may soon be brought to a similar level of accuracy, detail, and robustness as is commonly expected in external dose treatment planning. CONCLUSION: For this study we developed a code with a user-friendly interface that works on several nuclear medicine imaging platforms and provides timely patient-specific dose information to the physician and medical physicist. Future therapy with internal emitters should use a 3D dose calculation approach, which represents a significant advance over dose information provided by the standard geometric phantoms used for more than 20 y (which permit reporting of only average organ doses for certain standardized individuals)

Monoclonal antibodies in the treatment of hematologic malignancies: radiation dosimetry aspects.

A number of therapeutic agents in nuclear medicine are currently attracting considerable interest, including several for the treatment of hematologic and nonhematologic malignancies. A knowledge of the radiation dose received by different organs in the body is essential to the optimization of the therapy for each patient; one wants to maximize the dose to the malignant tissue while minimizing the dose to critical healthy tissues and avoiding any toxic response therein. In this paper, current methods for calculating radiation doses will be discussed and evaluated. In almost all nuclear medicine therapy, and particularly in this application, dose to the active marrow is of paramount concern. Specific focus on current bone marrow dose models and their ability to predict observed marrow toxicity in patient populations to date will be discussed. The paper will focus on current and possible future dosimetry practice in therapeutic nuclear medicine, particularly as regards the treatment of hematologic malignancies.