First clinical implementation of real-time, real anatomy tracking and radiation beam control.

PURPOSE: We describe the acceptance testing, commissioning, periodic quality assurance, and workflow procedures developed for the first clinically implemented magnetic resonance imaging-guided radiation therapy (MR-IGRT) system for real-time tracking and beam control. METHODS: The system utilizes real-time cine imaging capabilities at 4 frames per second for real-time tracking and beam control. Testing of the system was performed using an in-house developed motion platform and a commercially available motion phantom. Anatomical tracking is performed by first identifying a target (a region of interest that is either tissue to be treated or a critical structure) and generating a contour around it. A boundary contour is also created to identify tracking margins. The tracking algorithm deforms the anatomical contour (target or a normal organ) on every subsequent cine frame and compares it to the static boundary contour. If the anatomy of interest moves outside the boundary, the radiation delivery is halted until the tracked anatomy returns to treatment portal. The following were performed to validate and clinically implement the system: (a) spatial integrity evaluation; (b) tracking accuracy; (c) latency; (d) relative point dose and spatial dosimetry; (e) development of clinical workflow for gating; and (f) independent verification by an outside credentialing service. RESULTS: The spatial integrity of the MR system was found to be within 2 mm over a 45-cm diameter field-of-view. The tracking accuracy for geometric targets was within 1.2 mm. The average system latency was measured to be within 394 ms. The dosimetric accuracy using ionization chambers was within 1.3% ± 1.7%, and the dosimetric spatial accuracy was within 2 mm. The phantom irradiation for the outside credentialing service had satisfactory results, as well. CONCLUSIONS: The first clinical MR-IGRT system was validated for real-time tracking and gating capabilities and shown to be reliable and accurate. Patient workflow methods were developed for efficient treatment. Periodic quality assurance tests can be efficiently performed with commercially available equipment to ensure accurate system performance.

Dosimetric variances anticipated from breathing- induced tumor motion during tomotherapy treatment delivery.

In their classic paper, Yu et al (1998 Phys. Med. Biol. 43 91) investigated the interplay between tumor motion caused by breathing and dynamically collimated, intensity-modulated radiation delivery. The paper's analytic model assumed an idealized, sinusoidal pattern of motion. In this work, we investigate the effect of tumor motion based on patients' breathing patterns for typical tomotherapy treatments with field widths of 1.0 and 2.5 cm. The measured breathing patterns of 52 lung- and upper-abdominal-cancer patients were used to model a one-dimensional motion. A convolution of the measured beam-dose profiles with the motion model was used to compute the dose-distribution errors, and the positive and negative dose errors were recorded for each simulation. The dose errors increased with increasing motion magnitude, until the motion was similar in magnitude to the field width. For the 1.0 cm and 2.5 cm field widths, the maximum dose-error magnitude exceeded 10% in some simulations, even with breathing-motion magnitudes as small as 5 mm and 10 mm, respectively. Dose errors also increased slightly with increasing couch speed. We propose that the errors were due to subtle drifts in the amplitude and frequency of breathing motion, as well as changes in baseline (exhalation) position, causing both over- and under-dosing of the target. The results of this study highlight potential breathing-motion-induced dose delivery errors in tomotherapy. However, for conventionally fractionated treatments, the dose delivery errors may not be co-located and may average out over many fractions, although this may not be true for hypofractionated treatments.

Multimodality image registration quality assurance for conformal three-dimensional treatment planning.

PURPOSE: We present a quality assurance methodology to determine the accuracy of multimodality image registration and fusion for the purpose of conformal three-dimensional and intensity-modulated radiation therapy treatment planning. Registration and fusion accuracy between any combination of computed tomography (CT), magnetic resonance (MR), and positron emission computed tomography (PET) imaging studies can be evaluated. METHODS AND MATERIALS: A commercial anthropomorphic head phantom filled with water and containing CT, MR, and PET visible targets was modified to evaluate the accuracy of multimodality image registration and fusion software. For MR and PET imaging, the water inside the phantom was doped with CuNO(3) and 18F-fluorodeoxyglucose (18F-FDG), respectively. Targets consisting of plastic spheres and pins were distributed throughout the cranium section of the phantom. Each target sphere had a conical-shaped bore with its apex at the center of the sphere. The pins had a conical extension or indentation at the free end. The contours of the spheres, sphere centers, and pin tips were used as anatomic landmark models for image registration, which was performed using affine coordinate-transformation tools provided in a commercial multimodality image registration/fusion software package. Four sets of phantom image studies were obtained: primary CT, secondary CT with different phantom immobilization, MR, and PET study. A novel CT, MR, and PET external fiducial marking system was also tested. RESULTS: The registration of CT/CT, CT/MR, and CT/PET images allowed correlation of anatomic landmarks to within 2 mm, verifying the accuracy of the registration software and spatial fidelity of the four multimodality image sets. CONCLUSIONS: This straightforward phantom-based quality assurance of the image registration and fusion process can be used in a routine clinical setting or for providing a working image set for development of the image registration and fusion process and new software.

Biologic dosimetry of bone marrow: induction of micronuclei in reticulocytes after exposure to 32P and 90Y.

UNLABELLED: Bone marrow is the dose-limiting organ in targeted radionuclide therapy. Hence, determination of the absorbed dose to bone marrow from incorporated radionuclides is a critical element in treatment planning. This study investigated the potential of the micronucleus assay in peripheral blood reticulocytes (MnRETs) as an in vivo biologic dosimeter for bone marrow. METHODS: After intravenous administration of 32P-orthophosphate or 90Y-citrate in Swiss Webster mice, DNA damage induced in bone marrow erythroblastoid cells was measured by subsequent scoring of MnRETs in peripheral blood. The response to exponentially decreasing dose rates was calibrated by irradiating animals with external 137Cs-gamma-rays. The gamma-ray dose rate was decreased exponentially, with the dose-rate decrease half-time corresponding to the effective clearance half-time (Te) of the radioactivity from the femoral bone (Te = 64 h for 90Y-citrate and Te = 255 h for 32P-orthophosphate). RESULTS: The maximum MnRETs frequency occurred on the second and third day after injection of 90Y-citrate and 32P-orthophosphate, respectively. The same pattern was observed for exponentially decreasing dose rates of 137Cs-gamma-rays. For each type of exposure, the maximum MnRETs frequency increased in a dose-dependent manner. Using the calibrated dosimeter, the initial dose rates to the marrow per unit of injected activity were 0.0020 cGy/h/kBq and 0.0026 cGy/h/kBq for 32P-orthophosphate and 90Y-citrate, respectively. CONCLUSION: Micronuclei in peripheral blood reticulocytes can be used as a noninvasive biologic dosimeter for measuring absorbed dose rate and absorbed dose to bone marrow from incorporated radionuclides.

Marrow toxicity of 33P-versus 32P-orthophosphate: implications for therapy of bone pain and bone metastases.

UNLABELLED: Several bone-seeking radiopharmaceuticals, such as 32P-orthophosphate, 89Sr-chloride, 186Re-1,1 hydroxyethylidene diphosphonate (HEDP), and 153Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP), have been used to treat bone pain. The major limiting factor with this modality is bone marrow toxicity, which arises from the penetrating nature of the high-energy beta particles emitted by the radionuclides. It has been hypothesized that marrow toxicity can be reduced while maintaining therapeutic efficacy by using radionuclides that emit short-range beta particles or conversion electrons. In view of the significant clinical experience with 32P-orthophosphate, and the similarity in pain relief afforded by 32P-orthophosphate and 89Sr-chloride, this hypothesis is examined in this study using 32P- and 33P-orthophosphate in a mouse femur model. METHODS: Survival of granulocyte macrophage colony-forming cells (GM-CFCs) in femoral marrow was used as a biologic dosimeter for bone marrow. 32P- and 33P-orthophosphate were administered intravenously, and GM-CFC survival was determined as a function of time after injection and, at the nadir, as a function of injected activity. The kinetics of radioactivity in the marrow, muscle, and femoral bone were also determined. The biologic dosimeter was calibrated by assessing GM-CFC survival at its nadir after chronic irradiation of Swiss Webster mice with exponentially decreasing dose rates of gamma rays (relative biologic effectiveness equivalent to that of beta particles) from a low-dose rate 137Cs irradiator. Dose-rate decrease half-times (Td) (time required for 137Cs gamma ray dose rate to decrease by one half) of 62, 255, and 425 h and infinity were used to simulate the dose rate patterns delivered by the radiopharmaceuticals as dictated by their effective clearance half-times from the mouse femurs. These data were used to experimentally determine the mean absorbed dose to the femoral marrow per unit injected activity. Finally, a theoretical dosimetry model of the mouse femur was developed, and the absorbed doses to the femoral marrow, bone, and endosteum were calculated using the EGS4 Monte Carlo code. RESULTS: When the animals were irradiated with exponentially decreasing dose rates of 137Cs gamma rays, initial dose rates required to achieve 37% survival were 1.9, 0.98, 0.88, and 0.79 cGy/h for dose rate decrease half-times of 62, 255, and 425 h and infinity, respectively. The D37 values were 144 +/- 15, 132 +/- 12, 129 +/- 3, and 133 +/- 10 cGy, respectively, compared with a value of 103 cGy for acute irradiation. When 32P and 33P were administered, the injected activities required to achieve 37% survival were 313 and 2,820 kBq, respectively. Theoretical dosimetry calculations show that 33P offers a 3- to 6-fold therapeutic advantage over 32P, depending on the source and target regions assumed. CONCLUSION: The low-energy beta-particle emitter 33P appears to offer a substantial dosimetric advantage over energetic beta-particle emitters (e.g., 32p, 89Sr, 186Re) for irradiating bone and minimizing marrow toxicity. This suggests that low-energy beta or conversion electron emitters may offer a substantial advantage for alleviation of bone pain as well as for specifically irradiating metastatic disease in bone.

Considerations in the selection of radiopharmaceuticals for palliation of bone pain from metastatic osseous lesions.

UNLABELLED: Bone pain is a common complication for terminal patients with bone metastases from prostate, lung, breast, and other malignancies. A multidisciplinary approach in treating bone pain is generally required, 1 which includes a combination of analgesic drug therapy, radiation therapy, hormonal therapy, and chemotherapy. Over the years, treatment of bone pain using bone-seeking radiopharmaceuticals has been explored extensively. Pharmaceuticals labeled with energetic 1-particle emitters such as 32p, 89Sr, 153Sm, and 186Re, in addition to the low-energy electron emitter 117mSn, have been studied for this purpose. Bone-marrow toxicity as a consequence of chronic irradiation by the energetic , particles is a general problem associated with this form of treatment. It is therefore desirable to identify radiochemicals that minimize the dose to the bone marrow and at the same time deliver therapeutic doses to the bone. METHODS: New S values (mean absorbed dose per unit cumulated activity) for target regions of human bone and marrow were used to ascertain the capacity of various radiochemicals to deliver a high bone dose while minimizing the marrow dose. The relative dosimetric advantage of a given radiopharmaceutical compared with a reference radiochemical was quantitated as a dosimetric relative advantage factor (RAF). Several radionuclides that emit energetic 1 particles (32p, 89Sr, 153Sm, 186Re, and 177Lu) and radionuclides that emit low-energy electrons or beta particles (169Er, 117mSn, and 33p) were evaluated. For these calculations, ratios of the cumulated activity in the bone relative to cumulated activity in the marrow alpha equal to 10 and 100 were used. RESULTS: When the radiopharmaceutical was assumed to be uniformly distributed in the endosteum and alpha was taken as 100 for both the reference and test radiochemicals, the RAF values compared with the reference radionuclide 32p were 1.0, 1.2, 1.4, 1.6, 1.7, 1.9, and 2.0 for 89Sr, 186Re, 153Sm, 177Lu, 169Er, 117mSn, and 33P, respectively. In contrast, when the radiopharmaceutical is assumed to be uniformly distributed in the bone volume, the RAF values for these 7 radionuclides were 1.1, 1.5, 2.4, 3.2, 4.5, 5.1, and 6.5, respectively. CONCLUSION: These results suggest that low-energy electron emitters such as 117mSn and 33P are more likely to deliver a therapeutic dose to the bone while sparing the bone marrow than are energetic beta emitters such as 32p and 89Sr. Therefore, radiochemicals tagged with low-energy electron or beta emitters are the radiopharmaceuticals of choice for treatment of painful metastatic disease in bone.

Abutment region dosimetry for serial tomotherapy.

PURPOSE: A commercial intensity modulated radiation therapy system (Corvus, NOMOS Corp.) is presently used in our clinic to generate optimized dose distributions delivered using a proprietary dynamic multileaf collimator (DMLC) (MIMiC) composed of 20 opposed leaf pairs. On our accelerator (Clinac 600C/D, Varian Associates, Inc.) each MIMiC leaf projects to either 1.00 x 0.84 or 1.00 x 1.70 cm2 (depending on the treatment plan and termed 1 cm or 2 cm mode, respectively). The MIMiC is used to deliver serial (axial) tomotherapy treatment plans, in which the beam is delivered to a nearly cylindrical volume as the DMLC is rotated about the patient. For longer targets, the patient is moved (indexed) between treatments a distance corresponding to the projected leaf width. The treatment relies on precise indexing and a method was developed to measure the precision of indexing devices. A treatment planning study of the dosimetric effects of incorrect patient indexing and concluded that a dose heterogeneity of 10% mm(-1) resulted. Because the results may be sensitive to the dose model accuracy, we conducted a measurement-based investigation of the consequences of incorrect indexing using our accelerator. Although the indexing provides an accurate field abutment along the isocenter, due to beam divergence, hot and cold spots will be produced below and above isocenter, respectively, when less than 300 degree arcs were used. A preliminary study recently determined that for a 290 degree rotation in 1 cm mode, 15% cold and 7% hot spots were delivered to 7 cm above and below isocenter, respectively. This study completes the earlier work by investigating the dose heterogeneity as a function of position relative to the axis of rotation, arc length, and leaf width. The influence of random daily patient positioning errors is also investigated. METHODS AND MATERIALS: Treatment plans were generated using 8.0 cm diameter cylindrical target volumes within a homogeneous rectilinear film phantom. The plans included both 1 and 2 cm mode, optimized for 300 degrees, 240 degrees, and 180 degrees gantry rotations. Coronal-oriented films were irradiated throughout the target volumes and scanned using a laser film digitizer. The central target irradiated in 1 cm mode was also used to investigate the effects of incorrect couch indexing. RESULTS: The dose error as a function of couch index error was 25% mm(-1), significantly greater than previously reported. The clinically provided indexing system yielded 0.10 mm indexing precision. The intrinsic dose distributions indicated that more heterogeneous dose distributions resulted from the use of smaller gantry angle ranges and larger leaf projections. Using 300 degrees gantry angle and 1 cm mode yielded 7% hot and 15% cold spots 7 cm below and above isocenter, respectively. When a 180 degree gantry angle was used, the values changed to 22% hot and 27% cold spots for the same locations. The heterogeneities for the 2 cm mode were 70% greater than the corresponding 1 cm values. CONCLUSIONS: While serial tomotherapy is used to deliver highly conformal dose distributions, significant dosimetric factors must be considered before treatment. The patient must be immobilized during treatment to avoid dose heterogeneities caused by incorrect indexing due to patient movement. Even under ideal conditions, beam divergence can cause significant abutment-region dose heterogeneities. The use of larger gantry angle ranges, smaller leaf widths, and appropriate locations of the gantry rotation axis can minimize these effects.

Radioprotection against lethal damage caused by chronic irradiation with radionuclides in vitro.

To examine the capacity of chemical protectors to mitigate damage caused by chronic irradiation by incorporated radionuclides in vitro, cells must be maintained in the presence of the protector during the course of the irradiation. Such long exposures to chemical protectors at concentrations high enough to afford protection usually results in extreme chemotoxicity. To overcome this problem, experimental conditions were developed to allow Chinese hamster V79 cells to be maintained in 5% DMSO for prolonged periods (up to 72 h) with no observable chemotoxicity. Under these conditions, the capacity of DMSO to protect against damage to V79 cells caused by unbound 32P and 3H2O and DNA-incorporated (131)IdU, [3H]dThd and 125IdU was examined. The dose modification factors for 32P, 3H2O, (131)IdU, [3H]dThd and 125IdU were 2.6+/-0.5, 2.3+/-0.3, 1.0+/-0.1, 1.16+/-0.07 and 1.07+/-0.02, respectively. These results show that 5% DMSO is capable of protecting cultured V79 cells against lethal damage caused by beta particles emitted by unbound 32P and 3H2O, whereas little or no protection is afforded against damage caused by beta particles emitted by DNA-incorporated (131)I and 3H or low-energy Auger electrons emitted by DNA-incorporated 125I.

Biological dosimetry of bone marrow for incorporated yttrium-90.

UNLABELLED: The biological response of bone marrow to incorporated radionuclides depends on several factors such as absorbed dose, dose rate, proliferation and marrow reserve. The determination of the dose rate and absorbed dose to bone marrow from incorporated radionuclides is complex. This research used survival of granulocyte-macrophage colony-forming cells (GM-CFCs) as a biological dosimeter to determine experimentally the dose rate and dose to bone marrow after administration of 90Y-citrate. METHODS: The radiochemical 90Y-citrate was administered intravenously to Swiss Webster mice. Biokinetics studies indicated that the injected 90Y quickly localized in the femurs (0.8% ID/femur) and cleared with an effective half-time of 62 hr. Subsequently, GM-CFC survival was determined as a function of femur uptake and injected activity. Finally, to calibrate GM-CFC survival as a biological dosimeter, mice were irradiated with external 137Cs gamma rays at dose rates that decreased exponentially with a half-time of 62 hr. RESULTS: Femur uptake was linearly proportional to injected activity. The survival of GM-CFCs was exponentially dependent on both the initial 90Y femur activity and the initial dose rate from external 137Cs gamma rays with 5.1 kBq/femur and 1.9 cGy/hr, respectively, required to achieve 37% survival. Thus, 90Y-citrate delivers a dose rate of 0.37 cGy/hr to the femoral marrow per kBq of femur activity and the dose rate decreased with an effective half-time of 62 hr. CONCLUSION: Survival of GM-CFCs can serve as a biological dosimeter to experimentally determine the dose rate kinetics in bone marrow.

Proliferation and the advantage of longer-lived radionuclides in radioimmunotherapy.

In our previous study we used the linear-quadratic model [J. Nucl. Med. 35, 1861 (1994)] to confirm our initial finding, based on the time-dose-fractionation model [J. Nucl. Med. 34, 1801 (1993)], that longer-lived radionuclides (e.g., 32P, 91Y) can offer a substantial therapeutic advantage over the shorter-lived radionuclides presently used in radioimmunotherapy (e.g., 90Y). The original calculations using the linear-quadratic (LQ) model did not account for proliferation of the tumor and critical bone marrow tissues. It has been suggested that inclusion of a proliferation term in the LQ model can have a substantial impact on the biologically effective dose (BED). With this in mind, we have reexamined the therapeutic efficacy of longer versus short-lived radionuclides using the LQ model replete with proliferation terms for tumor and bone marrow. Relative advantage factors (RAF), which quantify the overall therapeutic advantage of a long-lived compared to short-lived radionuclide, were calculated accordingly. While the extrapolated initial dose rate required to achieve a given BED can be affected by the inclusion of proliferation terms for both the tumor and marrow, the relative advantage factors for the longer-lived radionuclides were not significantly affected. Longer-lived radionuclides such as (114m)In and 91Y are about three times more therapeutically effective than the shorter-lived 90Y which is currently used in RIT. In other words, for a given therapeutic effect in the tumor, a longer-lived radionuclide can result in a lower deleterious effect to the bone marrow than a short-lived radionuclide. Given that bone marrow is generally considered to be the dose-limiting organ, these results have important implications for radioimmunotherapy.

Design and performance characteristics of an experimental cesium-137 irradiator to simulate internal radionuclide dose rate patterns.

UNLABELLED: When radionuclides are administered internally, the biological effect can depend on the total absorbed dose and the rate at which it is delivered. A 137Cs irradiator was designed to deliver dose-rate patterns that simulate those encountered in radionuclide therapy. METHODS: An 18-Ci 137Cs irradiator was fitted with a computer-controlled mercury attenuator that facilitated changes in dose rates as desired. The absorbed dose and dose rates were calibrated with MOSFET dosimeters customized for low dose-rates. RESULTS: Initial dose rates ranging from 0.01-30 cGy/hr can be delivered depending on the location of the cage in the irradiator and the thickness of the mercury in the attenuator system. To demonstrate the irradiator system's capability to deliver dose-rate patterns encountered in radionuclide therapy, a simulation was performed where the dose rate initially increased exponentially followed by an exponential decrease in the dose rate. CONCLUSION: The irradiator system is well-suited to expose small animals to any dose-rate pattern, thereby facilitating calibration of biological dosimeters (e.g., cell survival, chromosome aberrations), which can be used to measure the absorbed dose to a target tissue after administration of radionuclides.

Radiotoxicity of gadolinium-148 and radium-223 in mouse testes: relative biological effectiveness of alpha-particle emitters in vivo.

The biological effects of radionuclides that emit alpha particles are of considerable interest in view of their potential for therapy and their presence in the environment. The present work is a continuation of our ongoing effort to study the radiotoxicity of alpha-particle emitters in vivo using the survival of murine testicular sperm heads as the biological end point. Specifically, the relative biological effectiveness (RBE) of very low-energy alpha particles (3.2 MeV) emitted by 148Gd is investigated and determined to be 7.4 +/- 2.4 when compared to the effects of acute external 120 kVp X rays. This datum, in conjunction with our earlier results for 210Po and 212Pb in equilibrium with its daughters, is used to revise and extend the range of validity of our previous RBE-energy relationship for alpha particles emitted by tissue-incorporated radionuclides. The new empirical relationship is given by RBE alpha = 9.14 - 0.510 E alpha where 3 < E alpha < 9 MeV. The validity of this empirical relationship is tested by determining the RBE of the prolific alpha-particle emitter 223Ra (in equilibrium with its daughters) experimentally in the same biological model and comparing the value obtained experimentally with the predicted value. The resulting RBE values are 5.4 +/- 0.9 and 5.6, respectively. This close agreement strongly supports the adequacy of the empirical RBE-E alpha relationship to predict the biological effects of alpha-particle emitters in vivo.

Effects of a 1.5-Tesla static magnetic field on spermatogenesis and embryogenesis in mice.

RATIONALE AND OBJECTIVES: There is a trend toward the use of higher magnetic field strengths in magnetic resonance imaging procedures. Considering this trend and the lack of consensus on the biologic effects of static magnetic fields, it is of considerable interest to examine the biologic effects of a 1.5-tesla (T) static magnetic field on spermatogenesis and embryogenesis in mice. METHODS: Male and pregnant female Swiss Webster mice were exposed to a 1.5-T static magnetic field for 30 minutes. Effects on spermatogenesis in male mice were investigated by counting testicular spermheads and epididymal spermhead shape-abnormalities as a function of time after exposure. Pregnant female mice were exposed to the field at the two-cell embryo stage, sacrificed immediately, and the ability of these preimplantation embryos to mature into blastocysts was examined in vitro. RESULTS: Exposure to the static 1.5-T magnetic field caused a statistically significant reduction (15%) in testicular sperm on the 16th and 29th days after exposure. However, the increase in spermhead shape abnormalities above normal control values was minimal. A substantial effect was noted on the development of preimplantation embryos with a survival fraction of 0.56 compared with controls. CONCLUSIONS: A 30-minute exposure to a 1.5-T static magnetic field appears to cause some deleterious effects on spermatogenesis and embryogenesis in mice.

Radioprotection by DMSO against the biological effects of incorporated radionuclides in vivo--Comparison with other radioprotectors and evidence for indirect action of Auger electrons.

Dimethyl sulfoxide (DMSO) was studied for its capacity to protect against the biological effects of chronic irradiation by incorporated radionuclides. Spermatogenesis in mice was used as experimental model and spermatogonial cell survival was the biological endpoint. DMSO was injected intratesticularly 4 h prior to a similar injection of the radiochemical and the spermhead survival determined. Iodine-125 was localized in either the cytoplasm (H125IPDM) or in the DNA (125IUdR) of the testicular cells. Protection was observed against the high-LET type effects of DNA-bound 125I as well as the low-LET effects of cytoplasmically localized 125I with dose modification factors (DMF) of 3.1+/-1.0 and 4.4+/-1.0 respectively. No protection (DMF = 1.1+/-0.1) was observed against the effects of high-LET 5.3 MeV alpha particles of 210Po. The present findings provide supporting evidence that the mechanism responsible for the extreme biological damage caused by DNA-bound Auger emitters is largely radical mediated and therefore indirect in nature.

Calculation of equivalent dose for Auger electron emitting radionuclides distributed in human organs.

Radionuclides that emit Auger electrons can be extremely radiotoxic depending on the subcellular distribution of the radiochemical. Despite this, ICRP 60 provides no guidance in the calculation of equivalent dose H(T) for Auger electrons. The recent report by the American Association of Physicists in Medicine recommends a radiation weighting factor wR of 20 for stochastic effects caused by Auger electrons, along with a method of calculating the equivalent dose that takes into account the subcellular distribution of the radionuclide. In view of these recommendations, it is important to reevaluate equivalent doses from Auger electron emitters. The mean absorbed dose per unit cumulated activity (S-value) from Auger electrons and other radiations is calculated for ninety Auger-electron-emitting radionuclides distributed in human ovaries, testes and liver. Using these S-values, and the formalism given in the recent AAPM report, the dependence of the organ equivalent doses on subcellular distribution of the Auger electron emitters is examined. The results show an increase in the mean equivalent dose for Auger electron emitters when a significant fraction of the organ activity localizes in the DNA.

Generalized approach to absorbed dose calculations for dynamic tumor and organ masses.

UNLABELLED: Tumor absorbed dose calculations in radionuclide therapy are presently based on the assumption of static tumor mass. This work examines the effect of dynamic tumor mass (growth and/or shrinkage) on the absorbed dose. METHODS: Tumor mass kinetic characteristics were modeled with the Gompertz equation to simulate tumor growth and an additional exponential term to accommodate tumor shrinkage that may result as a consequence of therapy. RESULTS: Correction factors, defined as the ratio of the absorbed dose, which was calculated by considering tumor mass dynamics, to the absorbed dose, which was calculated by assuming static mass, are presented for 1- and 100-g tumors with different tumor mass kinetics. The dependence of the correction factor on the effective half-life Te of the radioactivity in the tumor and the tumor shrinkage half-time Ts was examined. The correction factors for the 1-g tumor were > 1 for short Ts and Te. In contrast, the correction factor was less than 1 for long Ts ( > 9 days). The dose correction factors for the 100-g tumor were > 1 for all Ts and Te. Finally, the dosimetric method for dynamic masses is illustrated with experimental data on Chinese hamster V79 multicellular spheroids that were treated with 3H. CONCLUSION: Correction factors as high as about 10 are likely when Te and Ts are short. As Ts increases beyond 20 days, the importance of dynamic mass diminishes because most of the activity decays before the mass changes appreciably. In some cases, mass dynamics should be taken into account when the absorbed dose to tumors is estimated.

Radioprotection against biological effects of internal radionuclides in vivo by S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET).

UNLABELLED: Radionuclides employed in diagnostic and therapeutic nuclear medicine impart radiation energy to tissue over an extended period of time, which depends on the physical half-life and the biological properties of the radiochemical employed. It is therefore important to examine the capacity of chemical radioprotectors to mitigate damage caused by chronic irradiation by incorporated radionuclides. METHODS: Spermatogenesis in mouse testis is used as the experimental model, and spermatogonial cell survival as measured by testicular spermhead count is the biological end point. The capacity of S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET) to mitigate radiation damage caused by chronic irradiation by the radiochemicals 125IUdR, H125IPDM and 210Po-citrate, is investigated. RESULTS: The radioprotection provided by AET is substantial and similar for both of the radioiodinated compounds with dose modification factors (DMF) of 4.0 +/- 1.2 for 125IUdR and 3.4 +/- 0.4 for H125IPDM. In contrast, the damage caused by 210Po alpha particles is protected against to a lesser degree (DMF = 2.4 +/- 0.5). CONCLUSION: The present radioprotection data for AET, in conjunction with our earlier findings for the chemical protectors cysteamine and vitamin C in the same experimental model, suggest that such compounds may be clinically useful as mitigating agents against biological damage caused by incorporated radionuclides. The observed DMFs for AET also support our earlier premise that the mechanism by which DNA-incorporated Auger emitters impart biological damage is primarily radical mediated, and hence indirect in nature.

Relative biological effectiveness of 99mTc radiopharmaceuticals.

The radiotoxicity of three 99mTc-labeled compounds is investigated using spermatogenesis in mouse testis as the experimental model, and spermatogonial cell survival as the biological end point. The radiopharmaceuticals studied are pertechnetate (99mTcO4-), pyrophosphate (99mTc-PYP), and hydroxyethylene diphosphate (99mTc-HDP). The mean lethal doses at 37% survival (D37) are 0.70 +/- 0.06, 0.84 +/- 0.13, and 0.59 +/- 0.08 Gy for 99mTcO4-, 99mTc-PYP, and 99mTc-HDP, respectively. When these results are compared with the D37 value obtained with external x rays or internal gamma rays, the relative biological effectiveness (RBE) of these compounds are 0.94 +/- 0.09, 0.79 +/- 0.13, and 1.1 +/- 0.16, respectively. These results show that the radiotoxicity of 99mTc in mouse testis is essentially similar to that of low-LET radiations (i.e., RBE approximately 1). To understand these results, the distribution of these radiocompounds in the testis is determined and correlated with the observed RBE values. The expected range of RBE values for 99mTc radiopharmaceuticals in organs is 0.95 to 1.5, depending on the fraction of organ activity that is bound to DNA. This suggests that the Auger electrons emitted in the decay of 99mTc are not capable of causing extreme toxicity in vivo. These results provide further support for 99mTc as the radionuclide of choice for imaging in nuclear medicine.

Application of the linear-quadratic model to radioimmunotherapy: further support for the advantage of longer-lived radionuclides.

UNLABELLED: Radioimmunotherapy (RIT), as it is currently practiced, delivers low doses to tumors primarily because of dose-limiting bone marrow toxicity. The biologic effectiveness of RIT depends on the total dose, dose rate and the fractionation schedule of the radiolabeled antibodies administered. METHODS: An approach based on the linear-quadratic (LQ) model, which is currently used in conventional radiotherapy, is advanced for treatment planning in RIT. This approach incorporates repair rates, radiosensitivity of the tissues, biologic half-lives of the antibodies, physical half-lives of the radionuclides, dose rates and total doses needed for a given biologically effective dose. The concept of a relative advantage factor (RAF) is introduced to quantify the therapeutic gain that can be realized by using longer-lived radionuclides instead of the shorter-lived counterparts currently in use. RESULTS: RAFs are calculated for different biologic and physical half-lives, and values as high as 3 to 5 can be attained when longer-lived radionuclides are used. The RAFs predicted by the LQ model reaffirm the authors' earlier conclusion based on the time-dose-fractionation approach that relatively long-lived radionuclides coupled to monoclonal antibodies are indeed more likely to deliver therapeutically effective doses to tumors. Several radionuclides are evaluated in this context. CONCLUSION: The authors maintain that 32P is the most promising isotope and the optimal physical half-life is about two to three times the biologic clearance half-life of the antibodies in the tumor.

Vitamins as radioprotectors in vivo. II. Protection by vitamin A and soybean oil against radiation damage caused by internal radionuclides.

Tissue-incorporated radionuclides impart radiation energy over extended periods of time depending on their effective half-lives. The capacity of vitamin A dissolved in soybean oil to protect against the biological effects caused by internal radionuclides is investigated. The radiochemicals examined are DNA-binding 125IdU, cytoplasmically localized H125IPDM and the alpha-particle emitter 210Po citrate. As in our previous studies, spermatogenesis in mice is used as the experimental model and spermatogonial cell survival is the biological end point. Surprisingly, soybean oil itself provides substantial and equal protection against the Auger effect of 125IdU, which is comparable to a high-LET radiation effect, as well as the low-LET effects of H125IPDM, the dose modification factors (DMFs) being 3.6 +/- 0.9 (SEM) and 3.4 +/- 0.9, respectively. The protection afforded by the oil against the effects of 5.3 MeV alpha particles emitted by 210Po is also significant (DMF = 2.2 +/- 0.4). The presence of vitamin A in the oil further enhanced the radioprotection against the effect of 125IdU (DMF = 4.8 +/- 1.3) and H125IPDM (DMF = 5.1 +/- 0.6); however, no enhancement is provided against the effects of alpha particles. These interesting results with soybean oil and vitamin A, together with data on the subcellular distribution of the protectors, provide clues regarding the mechanistic aspects of the protection. In addition, the data for vitamin A reaffirm our earlier conclusion that the mechanism by which DNA-bound Auger emitters impart biological damage is primarily indirect in nature.