Dosimetry and toxicity of samarium-153-EDTMP administered for bone pain due to skeletal metastases.

UNLABELLED: Palliation of bone pain in patients with cancer metastatic to bone is being evaluated in several cancer centers by the administration of the bone-seeking phosphonate ethylenediaminetetramethylenephosphonic acid (EDTMP) chelated with the beta particle-emitting radionuclide 153Sm. METHODS: In this study, 153Sm-EDTMP was intravenously injected into 19 patients over a 1-min period. Patients received up to four injections of 18.5 MBq (0.5 mCi) or 37 MBq (1.0 mCi) per kilogram of body weight. Skeletal retention was calculated from urinary excretion. RESULTS: No uptake of 153Sm-EDTMP in nonskeletal tissues was observed in whole-body gamma camera images. The mean skeletal uptake for all patients was 54% +/- 16% of the injected dose (%ID). This resulted in the bone marrow receiving 89 cGy/GBq +/- 27 cGy/GBq (3.28 cGy/mCi +/- 0.99 cGy/mCi), with calculated marrow doses ranging from 27 cGy to 338 cGy. For each patient, the estimated radiation absorbed dose to the marrow was correlated to the percent decrease in platelet number, ranging from 7.4% to 78.9%. CONCLUSION: Since the deviation of uptake between the four injections for a given patient (7.6% ID) was less than the deviation for all patients (16% ID), the initial dose may be used to estimate the skeletal uptake for the remaining doses. These radiation dose estimates permit patients at risk to be identified prior to reaching myelotoxicity and develop dose-response models. Thirteen patients (68%) reported significant pain relief from this radionuclide therapy. Bone pain appears to be alleviated by 153Sm-EDTMP with limited red marrow doses and no toxic effects in other organs.

Pharmacokinetics, dosimetry and toxicity of holmium-166-DOTMP for bone marrow ablation in multiple myeloma.

UNLABELLED: In this Phase I clinical trial, six multiple myeloma patients who had not responded to conventional therapy and were scheduled for bone marrow transplantation received a bone-seeking radiopharmaceutical for bone marrow ablation. The pharmacokinetics, dosimetry, and toxicity of this radiopharmaceutical were studied. METHODS: Patients received from 519 mCi to 2.1 Ci (19.2 GBq to 77.7 GBq) of holmium-166 (166Ho) complexed with a bone-seeking agent, DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid). The reproducibility of pharmacokinetics from multiple injections of 166Ho-DOTMP administered to these myeloma patients was demonstrated from blood (r2 = 0.926) and whole-body retention (r2 = 0.983), which allowed therapeutic parameters to be determined from a diagnostic study. RESULTS: Over 50% of the 166Ho-DOTMP injected dose was excreted within 2-3 hr postinjection, increasing to 75%-85% over a 24-hr period. Rapid blood clearance minimized radiation dose to nontarget tissue: less than 10% of the injected activity was retained in the blood pool at 1 hr postinjection, and less than 2% remained after 5 hr. The total radiation absorbed dose delivered to the bone marrow for the six patients ranged from 7.9 Gy to 41.4 Gy. CONCLUSION: All patients demonstrated severe bone marrow toxicity with a white blood cell (WBC) count < 1,000 cells/microliters, two patients exhibited marrow ablation (WBC count < 100 cells/microliters), and no other toxicity > or = grade 2 was observed in any of the patients.

Dosimetry considerations of bone-seeking radionuclides for marrow ablation.

Marrow ablation by radionuclide therapy for patients requiring bone marrow transplantation is possible by injecting bone-seeking radiopharmaceuticals. For each radionuclide under consideration, one should determine the (1) amount of activity required to deliver a given radiation dose to marrow, (2) waiting period before reinfusion to limit the radiation dose to the transplant marrow to an acceptable level, and (3) dose to other critical organs. In an attempt to answer these questions, dose estimates for several radionuclides of interest (32P, 90Y, 153Sm, 166Ho, 186Re, and 188Re) have been calculated. All doses are derived following the MIRD methodology. Biodistribution data of 153Sm-labeled phosphates in the rat are used to estimate uptake of similar radiopharmaceuticals in humans. Typically the skeleton retains 50% of the injected activity and 50% is excreted rapidly through the urine, permitting delivery of ablation doses to the marrow, with tolerable doses to other organs. Skeletal retention data measured from a diagnostic dose can be used to calculate the activity required to deliver a desired marrow ablation dose consistent with toxicity limits set by other critical organs.

MLC dosimetric characteristics for small field and IMRT applications.

The objective of this work was to measure the performance characteristics of a double-focus multileaf collimator (MLC) for intensity modulated radiation therapy (IMRT), specifically the variation in penumbra and leakage for narrow fields as a function of field position over a 20x27 cm space available for segmented MLC IMRT. Measurements were made with 6 MV x rays through a MLC containing 29 leaf pairs (27 pairs of 1 cm width), and EDR2 film at 10 cm depth in solid water at 100 cm SAD. Films were digitized with 0.17 mm resolution and converted to dose. Interleaf and intraleaf transmission were measured along 11 vertical profile locations. Leaf-end transmission was measured along horizontal profiles for each of 9 different leaf abutments, traveling over a 20 cm range. In-plane penumbra measurements were made through a single leaf retracted, for 7 different leaves. Cross-plane penumbra (leaf-end) measurements were made for all 27 leaf pairs, where the 1 cm field width was placed in 11 different off-axis positions (20 cm range). Interleaf leakage (range 1.0%-1.5%), intraleaf transmission (range 0.6%-0.8%), and leaf-end transmission (range 0.8%-2.7%) were consistent for all leaf pairs at a given abutment position. The penumbra for these 1-cm-wide fields was measured to be 0.36 cm+/-0.03 cm for 99% of the measurements. In conclusion, the penumbra and leakage of the double-focus MLC were remarkably consistent for the range of leaf positions studied, producing dosimetric characteristics that are well suited for IMRT segments where opposing leaf pairs are often separated by 10 mm or less.

MLC quality assurance techniques for IMRT applications.

Intensity modulated radiotherapy (IMRT) requires extensive knowledge of multileaf collimator (MLC) leaf positioning accuracy, precision, and long-term reproducibility. We have developed a technique to efficiently measure the absolute position of each MLC leaf, over the range of leaf positions utilized in IMRT, based on dosimetric information. A single radiographic film was exposed to 6 MV x-rays for twelve exposures: one open field with a radio-opaque marker tray present, and eleven fields (1 x 28 cm strips via 1 cm gaps between opposed leaf pairs) separated by 2 cm center to center. The process was repeated while varying direction of leaf travel; each film was digitized using a commercial film dosimetry system. The digital images were manipulated to remove translation and rotation of the film data with respect to the collimator coordinate system by extraction of radiation dose profiles perpendicular to the MLC leaf motion and measuring the center of the x-ray leakage between leaves. Radiation dose profiles in the direction of leaf motion were acquired through the center of each leaf pair (leaves 2-28), which provided leaf position information every 2 cm with 0.2 mm precision. Nine separate leaf reproducibility studies over a 90 day period which evaluated 600 measurement points on each film show 0.3 mm precision for 95% confidence, while hysteresis studies show 0.5 mm precision. Absolute leaf position error measurements demonstrated a radial dependence, with a maximum of 1.5 mm at 16.4 cm from central axis, due to rotational error at calibration. Recalibration of the MLC leaves based utilizing this tool yields absolute leaf position measurements where 91.5% of all leaves/positions were within 0.5 mm, with a mean error of 0.1 mm and a maximum error less than 1.0 mm.

Radiation dose distribution within the bone marrow of patients receiving holmium-166-labeled-phosphonate for marrow ablation.

The primary objective of this work was to estimate the absorbed dose distribution to the bone marrow of six multiple myeloma patients who received holmium-166 (166Ho) DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid) for the purpose of bone marrow ablation. A methodology based on gamma camera images was developed to estimate the regional absorbed dose distributions delivered to the bone marrow, and this was compared with values calculated from the MIRD technique and bone marrow biopsies. The activity concentration in various skeletal regions was calculated from the activity in the region of interest (ROI) drawn on whole body gamma camera images, and the mass of bone in each ROI was derived from a dual x-ray absorptiometry image. The radiation absorbed dose to the bone marrow was calculated from this activity concentration using an adaptation of Bragg-Gray cavity theory. The radiation absorbed dose delivered to the bone marrow in the six patients calculated from the MIRD "S" factors ranged from 15.0 to 46.3 Gy. The gamma camera measured activity concentration in skeletal regions predominantly composed of trabecular bone was approximately five to six times higher than that in cortical regions. The skeletal activity concentration in each patient ranged from highs in such regions as the ribs to lows in such regions as the shin and foot by a factor of nearly 20, producing a heterogeneous distribution of absorbed dose within the marrow. Dose volume histograms calculated for these patients indicated that 15%-20% of the marrow received an absorbed dose significantly larger than the average value, while 5%-10% of the marrow received a substantially lower dose. Weighted mean dose estimates from the regional technique were typically 30% greater than the average dose estimates calculated with the MIRD "S" factors. Finally, absorbed dose estimates for the marrow calculated from the regional technique correlated more closely with the clinical response of blood cells and abnormal proteins measured in bone marrow aspirates and peripheral blood samples than estimates from the MIRD "S" factors.

Improved conjugate view quantitation of I-131 by subtraction of scatter and septal penetration events with a triple energy window method.

The majority of radiation absorbed dose estimates for radioimmunotherapy (RIT) with I-131 labeled antibodies have been calculated based on in vivo quantitation of activity using the conjugate view approach with planar Anger camera images. Scatter and septal penetration events contributed by a small fraction of high-energy photons emitted by I-131 with an energy exceeding 600 KeV lead to a significant degradation of I-131 images acquired with an Anger camera, which blurs the images of uptake sites and complicates the definition of background regions. The objective of this study was to evaluate a triple energy window (TEW) subtraction method that has been used to remove these interfering events from I-131 images. In the method, a primary photopeak image for I-131 is obtained after sequential subtraction of septal penetration and scatter events by using scatter multipliers derived from a photopeak window and two adjacent scatter window images. Qualitative improvement in image contrast was demonstrated with this technique, together with more accurate and reproducible quantitation for I-131 in the organs of an abdominal phantom. This TEW scatter subtraction method can be used to provide more precise dosimetry estimates for radionuclide therapy and RIT with I-131.

Quantitative imaging of holmium-166 with an Anger camera.

The objective of this study was to develop a quantitative Anger camera imaging approach for 166Ho in the skeletal system of patients. A dual energy window method was designed to subtract the interference from septal penetration and bremsstrahlung events in Anger camera images acquired with the 80 keV x-rays emitted by 166Ho. The validity of this scatter subtraction method for 166Ho images was demonstrated as improvements of the line spread function and modulation transfer function. Camera sensitivity was found to be nearly independent of source-to-collimator distance only for images acquired with a high-energy collimator. Studies in an Alderson abdominal water phantom demonstrated scatter subtraction can provide quantitative Anger camera images of 166Ho with a scatter multiplier of k = 1.0 and a correction for attenuation. Attenuation correction factors derived from a transmission image were measured for the phantom and verified with water-equivalent blocks of known thickness. Whole-body scan images of 166Ho localized in the skeletal system of patients were significantly improved with this simple scatter subtraction method, and when used to estimate the activity distribution within separate bone regions of the skeleton.

Validation of a dose-point kernel convolution technique for internal dosimetry.

The objective of this study was to validate a dose-point kernel convolution technique that provides a three-dimensional (3D) distribution of absorbed dose from a 3D distribution of the radionuclide 131I. A dose-point kernel for the penetrating radiations was calculated by a Monte Carlo simulation and cast in a 3D rectangular matrix. This matrix was convolved with the 3D activity map furnished by quantitative single-photon-emission computed tomography (SPECT) to provide a 3D distribution of absorbed dose. The convolution calculation was performed using a 3D fast Fourier transform (FFT) technique, which takes less than 40 s for a 128 x 128 x 16 matrix on an Intel 486 DX2 (66 MHz) personal computer. The calculated photon absorbed dose was compared with values measured by thermoluminescent dosimeters (TLDS) inserted along the diameter of a 22 cm diameter annular source of 131I. The mean and standard deviation of the percentage difference between the measurements and the calculations were equal to -1% and 3.6%, respectively. This convolution method was also used to calculate the 3D dose distribution in an Alderson abdominal phantom containing a liver, a spleen, and a spherical tumour volume loaded with various concentrations of 131I. By averaging the dose calculated throughout the liver, spleen, and tumour the dose-point kernel approach was compared with values derived using the MIRD formalism, and found to agree to better than 15%.

Simulation of angular and energy distributions of the PTB beta secondary standard.

Calculations and measurements have been performed to assess radiation doses delivered by the PTB Secondary Standard that employs 147Pm, 204Tl, and 90Sr:90Y sources in prescribed geometries, and features "beam-flattening" filters to assure uniformity of delivered doses within a 5-cm radius of the axis from source to detector plane. Three-dimensional, coupled, electron-photon Monte Carlo calculations, accounting for transmission through the source encapsulation and backscattering from the source mounting, led to energy spectra and angular distributions of electrons penetrating the source encapsulation that were used in the representation of pseudo sources of electrons for subsequent transport through the atmosphere, filters, and detectors. Calculations were supplemented by measurements made using bare LiF TLD chips on a thick polymethyl methacrylate phantom. Measurements using the 204Tl and 90Sr:90Y sources revealed that, even in the absence of the beam-flattening filters, delivered dose rates were very uniform radially. Dosimeter response functions (TLD:skin dose ratios) were calculated and confirmed experimentally for all three beta-particle sources and for bare LiF TLDs ranging in mass thickness from 10 to 235 mg cm-2.