MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response--implications for radionuclide therapy.

UNLABELLED: Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose-response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys. METHODS: The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity. RESULTS: Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and (166)Ho-phosphonate clinical investigations. CONCLUSION: Radionuclide therapy dose-response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.

Trilogy image-guided stereotactic radiosurgery.

Full integration of advanced imaging, noninvasive immobilization, positioning, and motion-management methods into radiosurgery have resulted in fundamental changes in therapeutic strategies and approaches that are leading us to the treatment room of the future. With the introduction of image-guided radiosurgery (IGRS) systems, such as Trilogy, physicians have for the first time a practical means of routinely identifying and treating very small lesions throughout the body. Using new imaging processes such as positron emission tomography/computed tomography (PET/CT) scans, clinics may be able to detect these lesions and then eradicate them with image-guided stereotactic radiosurgery treatments. Thus, there is promise that cancer could be turned into a chronic disease, managed through a series of checkups, and Trilogy treatments when metastatic lesions reappear.

Dynamic targeting image-guided radiotherapy.

Volumetric imaging and planning for 3-dimensional (3D) conformal radiotherapy and intensity-modulated radiotherapy (IMRT) have highlighted the need to the oncology community to better understand the geometric uncertainties inherent in the radiotherapy delivery process, including setup error (interfraction) as well as organ motion during treatment (intrafraction). This has ushered in the development of emerging technologies and clinical processes, collectively referred to as image-guided radiotherapy (IGRT). The goal of IGRT is to provide the tools needed to manage both inter- and intrafraction motion to improve the accuracy of treatment delivery. Like IMRT, IGRT is a process involving all steps in the radiotherapy treatment process, including patient immobilization, computed tomography (CT) simulation, treatment planning, plan verification, patient setup verification and correction, delivery, and quality assurance. The technology and capability of the Dynamic Targeting IGRT system developed by Varian Medical Systems is presented. The core of this system is a Clinac or Trilogy accelerator equipped with a gantry-mounted imaging system known as the On-Board Imager (OBI). This includes a kilovoltage (kV) x-ray source, an amorphous silicon kV digital image detector, and 2 robotic arms that independently position the kV source and imager orthogonal to the treatment beam. A similar robotic arm positions the PortalVision megavoltage (MV) portal digital image detector, allowing both to be used in concert. The system is designed to support a variety of imaging modalities. The following applications and how they fit in the overall clinical process are described: kV and MV planar radiographic imaging for patient repositioning, kV volumetric cone beam CT imaging for patient repositioning, and kV planar fluoroscopic imaging for gating verification. Achieving image-guided motion management throughout the radiation oncology process requires not just a single product, but a suite of integrated products to manipulate all patient data, including images, efficiently and effectively.

A simple and reliable index for scoring rival stereotactic radiosurgery plans.

PURPOSE: A simple and robust index for ranking rival stereotactic radiosurgery plans is presented. METHODS: The radiosurgery plan score index, CGI (Conformity/Gradient Index), is an average of a conformity score and a gradient score. Computation of the CGI score is simple, requiring only three pieces of data: (1) the total volume irradiated to the prescription isodose level, (2) the volume of the target, and (3) the total volume irradiated at half of the prescription isodose level. The overall CGI Index is a simple function of these three pieces of data. RESULTS: When multiple sets of rival stereotactic radiosurgery plans were ranked with respect to this single score index, the resulting plan rankings closely matched the plan rankings according to biologic indices (calculated nontarget brain normal tissue complication probabilities). CONCLUSIONS: The CGI is a simple and fast plan evaluation tool that can assist the radiosurgery planner in evaluating and optimizing multiple candidate radiosurgery plans.

Ultrasound-guided extracranial radiosurgery: technique and application.

PURPOSE: Stereotactic radiosurgery is an effective treatment modality for many intracranial lesions, but target mobility limits its utility for extracranial applications. We have developed a new technique for extracranial radiosurgery based on optically guided three-dimensional ultrasound (3DUS). The 3DUS system provides the ability to image the target volume and critical structures in real time and determine any misregistration of the target volume with the linear accelerator. In this paper, we describe the system and its initial clinical application in the treatment of localized metastatic disease. METHODS AND MATERIALS: The extracranial stereotactic system consists of an ultrasound unit that is optically tracked and registered with the linear accelerator coordinate system. After an initial patient positioning based on computed tomographic (CT) simulation, stereotactic ultrasound images are acquired and correlated with the CT-based treatment plan to determine any soft-tissue shifts between the time of the planning CT and the actual treatment. Optical tracking is used to correct any patient offsets that are revealed by the real-time imaging. RESULTS: Preclinical testing revealed that the ultrasound-based stereotactic navigation system is accurate to within 1.5 mm in comparison with an absolute coordinate phantom. Between March 2001 and March 2002, the system was used to deliver extracranial radiosurgery to 17 metastatic lesions in 16 patients. Treatments were delivered in 1 or 2 fractions, with an average fractional dose of 16 Gy (range 12.5-24 Gy) delivered to the 80% isodose surface. Before each fraction, the target misalignment from isocenter was determined using the 3DUS system and the misalignments averaged over all patients were anteroposterior = 4.8 mm, lateral = 3.6 mm, axial = 2.1 mm, and average total 3D displacement = 7.4 mm (range = 0-21.0 mm). After correcting patient misalignment, each plan was delivered as planned using 6-11 noncoplanar fields. No acute complications were reported. CONCLUSIONS: A system for high-precision radiosurgical treatment of metastatic tumors has been developed, tested, and applied clinically. Optical tracking of the ultrasound probe provides real-time tracking of the patient anatomy and allows computation of the target displacement before treatment delivery. The patient treatments reported here suggest the feasibility and safety of the technique.

Bone marrow dosimetry using blood-based models for radiolabeled antibody therapy: a multiinstitutional comparison.

UNLABELLED: Standardization of marrow dosimetry is of considerable importance when estimating dose-response for a multicentered clinical trial involving radionuclide therapy. However, it is only within the past five years that the intercomparison of marrow dosimetry results among separate clinical trials that use the same agent has become scientifically feasible. In this work, we have analyzed reported marrow dosimetry results from radioimmunotherapy trials and recalculated marrow absorbed doses at a central facility using a standard blood model with patient-specific source data. The basic approach used in the American Association of Physicists in Medicine (AAPM)/Sgouros marrow dosimetry methodology was common to calculation performed at all participating institutions, including the central facility. Differences in dose estimates associated with starting assumptions and the exact implementation of the AAPM/Sgouros calculation methodology used by the source institutions and the central facility were quantified and compared. METHODS: Data from 22 patients enrolled in radiolabeled antibody clinical trials were randomly selected from 7 participating institutions for the assessment of marrow dose. The analysis was restricted to those patients who were treated with 131I- or 186Re-labeled antibody and had no marrow involvement. Calculation of bone marrow dose at each participating institution was unique to the trial or institution, but all used some form of the AAPM/Sgouros blood model approach. The central facility adopted a marrow dosimetry model based on the AAPM/Sgouros model for radiolabeled antibodies using the standard MIRD approach to the remainder-of-body contribution. A standardized approach to account for variations in patient mass was used for the remainder-of-body component. To simplify clinical implementation, regional marrow uptake and time-dependent changes in the marrow-to-blood concentration ratio were not included. Methods of formatting the collection of standard datasets useful in defining dose-response parameters are also presented. RESULTS: Bone marrow doses were calculated according to the method described for each of the 22 patients based on the patient-specific data supplied by the participating institutions. These values were then individually compared with the marrow doses originally reported by each institution. Comparison of the two calculation methods was expressed as a ratio of the marrow doses for each patient. The mean ratio for the dose estimates at the participating institution calculation compared with the central laboratory value was 0.920 +/- 0.259 (mean +/- SD), with a range from 0.708 to 1.202. CONCLUSION: The independent use of the AAPM/Sgouros method blood model approach to marrow dosimetry has brought these dose estimates to within 30% of the results obtained centrally compared with substantially higher uncertainties reported previously. Variations in calculation methodology or initial assumptions adopted by individual institutions may still contribute significant uncertainty to dose estimates, even when the same data are used as a starting point for the calculation comparison shown here. A clinically relevant, standard method for marrow dosimetry for radiolabeled antibodies is proposed as a benchmark for intercomparison purposes. A parameter sensitivity analysis and a summary discussion of the use of this model for potentially improving dose-response data correlation are also presented.

MIRD Pamphlet No 19: absorbed fractions and radionuclide S values for six age-dependent multiregion models of the kidney.

UNLABELLED: As one of the major organs of the excretory pathway, the kidneys represent a frequent source of radiopharmaceutical uptake in both diagnostic and therapeutic nuclear medicine. The unique organization of the functional tissues of the organ ensures transient changes in suborgan localization of renal activity. Current single-region dosimetric models of the kidneys, however, force the assumption of a uniform distribution of radioactivity across the entire organ. The average absorbed dose to the kidneys predicted by such models can misrepresent local regional doses to specific substructures. METHODS: To facilitate suborgan dosimetry for the kidneys, 6 new age-dependent multiregion kidney models are presented. The outer dimensions of the models conform to those used currently in single-region kidney models, whereas interior structures are defined for the renal cortex, the medullary pyramids with papillae (2 vertical and 3 horizontal), and the renal pelvis. Absorbed fractions of energy were calculated for both photon and electron sources (10 keV to 4 MeV) located in each source region within the 6 age-dependent models. The absorbed fractions were then used to assemble S values for radionuclides of potential interest in suborgan kidney dosimetry. RESULTS: For the adult, the absorbed dose to the renal cortex for (90)Y-labeled compounds retained within that subregion is approximately 1.3 times that predicted by the single-region kidney model, whereas the medullary dose is only 26% of that same single-region value. For compounds that are rapidly filtered in the kidneys, the renal cortex dose is approximately one-half of that predicted under the single-region model, whereas the tissues of the medullary pyramids receive an absorbed dose 1.5-1.8 times larger. CONCLUSION: The multiregion model described here permits estimates of regional kidney dose not previously supported by current single-region models. Full utilization of the new model, however, requires serial imaging of the kidneys with regions of interest assigned to the renal cortex and medulla.

Commissioning and quality assurance of an optically guided three-dimensional ultrasound target localization system for radiotherapy.

Recently, there has been proliferation of image-guided positioning systems for high-precision radiation therapy, with little attention given to quality assurance procedures for such systems. To ensure accurate treatment delivery, errors in the imaging, localization, and treatment delivery processes must be systematically analyzed. This paper details acceptance tests for an optically guided three-dimensional (3D) ultrasound system used for patient localization. While all tests were performed using the same commercial system, the general philosophy and procedures are applicable to all systems utilizing image guidance. Determination of absolute localization accuracy requires a consistent stereotactic, or three-dimensional, coordinate system in the treatment planning system and the treatment vault. We established such a coordinate system using optical guidance. The accuracy of this system for localization of spherical targets imbedded in a phantom at depths ranging from 3 to 13 cm was determined to be (average +/- standard deviation) AP = 0.2 +/- 0.7 mm, Lat = 0.9 +/- 0.6 mm, Ax = 0.6 +/- 1.0 mm. In order to test the ability of the optically guided 3D ultrasound localization system to determine the magnitude of an internal organ shift with respect to the treatment isocenter, a phantom that closely mimics the typical human male pelvic anatomy was used. A CT scan of the phantom was acquired, and the regions of interest were contoured. With the phantom on the treatment couch, optical guidance was used to determine the positions of each organ to within imaging uncertainty, and to align the phantom so the plan and treatment machine coordinates coincided. To simulate a clinical misalignment of the treatment target, the phantom was then shifted by different precise offsets, and an experimenter blind to the offsets used ultrasound guidance to determine the magnitude of the shifts. On average, the magnitude of the shifts could be determined to within 1.0 mm along each axis.

Dosimetry of high dose skeletal targeted radiotherapy (STR) with 166Ho-DOTMP.

A study was undertaken to determine the maximum tolerated dose of (166)Ho-DOTMP that could be administered safely, without negatively impacting marrow re-engraftment, in patients with multiple myeloma treated with melphalan prior to transplant. Ho-166 DOTMP is a tetraphosphonate that localizes rapidly to bone surface. The Ho-166 physical half-life is 26.8 hr and the maximum beta energy is 1.8 MeV. Standard dosimetry models were adapted for radiation absorbed dose estimates using data obtained from whole body counting of the low abundance photons emitted by (166)Ho. Eighty-three patients received high dose (166)Ho-DOTMP followed by melphalan and transplant of peripheral blood stem cells. Twenty-five patients also received 8 Gy total body radiation (TBI). Dosages administered ranged from 460 to 4476 mCi (166)Ho-DOTMP. Marrow dose was derived using the assumption that all radioactivity not excreted by 20 hours was localized to the bone surfaces, and applying the Eckerman bone and marrow dose model to the calculated bone residence times. The dosimetry of the urinary bladder and kidneys was important because of the rapid excretion of the non-targeted radioactivity via the urinary pathway. The dynamic bladder model was used for bladder wall surface dose, and the ICRP 53 kinetic model was used to model kidney kinetics with an additional blood component included. Marrow doses ranged from 13 to 59 Gy and successful hematapoietic recovery occurred. Bladder doses ranged from 4.7 to 157 Gy. Hemorrhagic cystitis occurred in some patients who received more than 40 Gy to the bladder wall surface. Bladder irrigation was successful in protecting patients from bladder toxicity. Kidney doses ranged from 0.5-7.9 Gy. Kidney toxicity in the form of thrombotic microangiopathy with renal dysfunction was observed, with the severity being related to Ho-166-DOTMP radiation dose and probably the dose rate as well. In a future trial, kidney dosimetry will be assessed using early serial gamma camera imaging and modifications will be implemented to reduce renal toxicity.

Voxeldoes: a computer program for 3-D dose calculation in therapeutic nuclear medicine.

A computer program, VoxelDose, was developed to calculate patient specific 3-D-dose maps at the voxel level. The 3-D dose map is derived in three steps: (i) The SPECT acquisitions are reconstructed using a filtered back projection method, with correction for attenuation and scatter; (ii) the 3-D cumulated activity map is generated by integrating the SPECT data; and (iii) a 3-D dose map is computed by convolution (using the Fourier Transform) of the cumulated activity map and corresponding MIRD voxel S values. To validate the VoxelDose software, a Liqui-Phil abdominal phantom with four simulated organ inserts and one spherical tumor (radius 4.2 cm) was filled with known activity concentrations of 111In. Four cylindrical calibration tubes (from 3.7 to 102 kBq/mL) were placed on the phantom. Thermoluminescent mini-dosimeters (mini-TLDs) were positioned on the surface of the organ inserts. Percent differences between the known and measured activity concentrations were determined to be 12.1 (tumor), 1.8 (spleen), 1.4, 8.1 (right and left kidneys), and 38.2% (liver), leading to percent differences between the calculated and TLD measured doses of 41, 16, 3, 5, and 62%. Large differences between the measured and calculated dose in the tumor and the liver may be attributed to several reasons, such as the difficulty in precisely associating the position of the TLD to a voxel and limits of the quantification method (mainly the scatter correction and partial volume effect). Further investigations should be performed to better understand the impact of each effect on the results and to improve absolute quantification. For all other organs, activity concentration measurements and dose calculations agree well with the known activity concentrations.