Prediction of therapy tumor-absorbed dose estimates in I-131 radioimmunotherapy using tracer data via a mixed-model fit to time activity.

BACKGROUND: For individualized treatment planning in radioimmunotherapy (RIT), correlations must be established between tracer-predicted and therapy-delivered absorbed doses. The focus of this work was to investigate this correlation for tumors. METHODS: The study analyzed 57 tumors in 19 follicular lymphoma patients treated with I-131 tositumomab and imaged with SPECT/CT multiple times after tracer and therapy administrations. Instead of the typical least-squares fit to a single tumor's measured time-activity data, estimation was accomplished via a biexponential mixed model in which the curves from multiple subjects were jointly estimated. The tumor-absorbed dose estimates were determined by patient-specific Monte Carlo calculation. RESULTS: The mixed model gave realistic tumor time-activity fits that showed the expected uptake and clearance phases even with noisy data or missing time points. Correlation between tracer and therapy tumor-residence times (r=0.98; p<0.0001) and correlation between tracer-predicted and therapy-delivered mean tumor-absorbed doses (r=0.86; p<0.0001) were very high. The predicted and delivered absorbed doses were within ± 25% (or within ± 75 cGy) for 80% of tumors. CONCLUSIONS: The mixed-model approach is feasible for fitting tumor time-activity data in RIT treatment planning when individual least-squares fitting is not possible due to inadequate sampling points. The good correlation between predicted and delivered tumor doses demonstrates the potential of using a pretherapy tracer study for tumor dosimetry-based treatment planning in RIT.

Staging of differentiated thyroid carcinoma using diagnostic 131I SPECT/CT.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of staging differentiated thyroid carcinoma (DTC) before initial radioiodine therapy using diagnostic radioiodine-131 ((131)I) scintigraphy with SPECT/CT and to determine the additional value of SPECT/CT. MATERIALS AND METHODS: Forty-eight patients (12 men and 36 women; age range, 17-82 years) with DTC underwent diagnostic (131)I planar imaging and SPECT/CT scintigraphy reinterpreted by two readers, one of whom was not blinded to patients' clinical details. Staging and scoring of carcinomas was done by use of TNM with three levels of sequential information: histopathologic analysis and chest radiograph data, planar images, and SPECT/CT data. Restaging based on the imaging findings was designated as "iTNM." RESULTS: Diagnostic (131)I scintigraphy allowed TNM staging of DTC before initial radioiodine therapy. Planar images detected previously unsuspected distant disease in four (50%) of eight patients with a score of M1. SPECT/CT changed the planar scan interpretation for 19 (40%) of 48 patients, detecting regional nodal metastases in four patients and clarifying equivocal focal neck uptake in 15 patients. Compared with histopathologic analysis and chest radiograph data, planar images and SPECT/CT changed the postsurgical DTC stage for 10 (21%) of 48 patients. SPECT/CT information changed the proposed (131)I therapeutic dose for 28 (58%) of 48 patients, on the basis of our department protocol. CONCLUSION: Diagnostic (131)I scintigraphy, planar images, and SPECT/CT complete the postsurgical staging of DTC. SPECT/CT reduces the number of equivocal diagnoses on planar imaging and improves the interpretation of (131)I scintigraphy. The consequent changes in TNM scores and staging should influence the (131)I dose prescribed at initial therapy.

131I-tositumomab radioimmunotherapy: initial tumor dose-response results using 3-dimensional dosimetry including radiobiologic modeling.

UNLABELLED: For optimal treatment planning in radionuclide therapy, robust tumor dose-response correlations must be established. Here, fully 3-dimensional (3D) dosimetry was performed coupling SPECT/CT at multiple time points with Monte Carlo-based voxel-by-voxel dosimetry to examine such correlations. METHODS: Twenty patients undergoing (131)I-tositumomab for the treatment of refractory B-cell lymphoma volunteered for the study. Sixty tumors were imaged. Activity quantification and dosimetry were performed using previously developed 3D algorithms for SPECT reconstruction and absorbed dose estimation. Tumors were outlined on CT at multiple time points to obtain absorbed dose distributions in the presence of tumor deformation and regression. Equivalent uniform dose (EUD) was calculated to assess the biologic effects of the nonuniform absorbed dose, including the cold antibody effect. Response for correlation analysis was determined on the basis of the percentage reduction in the product of the largest perpendicular tumor diameters on CT at 2 mo. Overall response classification (as complete response, partial response, stable disease, or progressive disease) used for prediction analysis was based on criteria that included findings on PET. RESULTS: Of the evaluated tumor-absorbed dose summary measures (mean absorbed dose, EUD, and other measures from dose-volume histogram analysis), a statistically significant correlation with response was seen only with EUD (r = 0.36 and P = 0.006 at the individual tumor level; r = 0.46 and P = 0.048 at the patient level). The median value of mean absorbed dose for stable disease, partial response, and complete response patients was 196, 346, and 342 cGy, respectively, whereas the median value of EUD for each of these categories was 170, 363, and 406 cGy, respectively. At a threshold of 200 cGy, both mean absorbed dose and EUD had a positive predictive value for responders (partial response + complete response) of 0.875 (14/16) and a negative predictive value of 1.0 (3/3). CONCLUSION: Improved dose-response correlations were demonstrated when EUD incorporating the cold antibody effect was used instead of the conventionally used mean tumor-absorbed dose. This work demonstrates the importance of 3D calculation and radiobiologic modeling when estimating absorbed dose for correlation with outcome.

Regularized reconstruction in quantitative SPECT using CT side information from hybrid imaging.

A penalized-likelihood (PL) SPECT reconstruction method using a modified regularizer that accounts for anatomical boundary side information was implemented to achieve accurate estimates of both the total target activity and the activity distribution within targets. In both simulations and experimental I-131 phantom studies, reconstructions from (1) penalized likelihood employing CT-side information-based regularization (PL-CT), (2) penalized likelihood with edge preserving regularization (no CT) and (3) penalized likelihood with conventional spatially invariant quadratic regularization (no CT) were compared with (4) ordered subset expectation maximization (OSEM), which is the iterative algorithm conventionally used in clinics for quantitative SPECT. Evaluations included phantom studies with perfect and imperfect side information and studies with uniform and non-uniform activity distributions in the target. For targets with uniform activity, the PL-CT images and profiles were closest to the 'truth', avoided the edge offshoots evident with OSEM and minimized the blurring across boundaries evident with regularization without CT information. Apart from visual comparison, reconstruction accuracy was evaluated using the bias and standard deviation (STD) of the total target activity estimate and the root mean square error (RMSE) of the activity distribution within the target. PL-CT reconstruction reduced both bias and RMSE compared with regularization without side information. When compared with unregularized OSEM, PL-CT reduced RMSE and STD while bias was comparable. For targets with non-uniform activity, these improvements with PL-CT were observed only when the change in activity was matched by a change in the anatomical image and the corresponding inner boundary was also used to control the regularization. In summary, the present work demonstrates the potential of using CT side information to obtain improved estimates of the activity distribution in targets without sacrificing the accuracy of total target activity estimation. The method is best suited for data acquired on hybrid systems where SPECT-CT misregistration is minimized. To demonstrate clinical application, the PL reconstruction with CT-based regularization was applied to data from a patient who underwent SPECT/CT imaging for tumor dosimetry following I-131 radioimmunotherapy.

Use of integrated SPECT/CT imaging for tumor dosimetry in I-131 radioimmunotherapy: a pilot patient study.

Integrated systems combining functional (single-photon emission computed tomography; SPECT) imaging with anatomic (computed tomography; CT) imaging have the potential to greatly improve the accuracy of dose estimation in radionuclide therapy. In this article, we present the methodology for highly patient-specific tumor dosimetry by utilizing such a system and apply it to a pilot study of 4 follicular lymphoma patients treated with I-131 tositumomab. SPECT quantification included three-dimensional ordered-subset expectation-maximization reconstruction and CT-defined tumor outlines at each time point. SPECT/CT images from multiple time points were coupled to a Monte Carlo algorithm to calculate a mean tumor dose that incorporated measured changes in tumor volume. The tumor shrinkage, defined as the difference between volumes drawn on the first and last CT scan (a typical time period of 15 days) was in the range 5%-49%. The therapy-delivered mean tumor-absorbed dose was in the range 146-334 cGy. For comparison, the therapy dose was also calculated by assuming a static volume from the initial CT and was found to underestimate this dose by up to 47%. The agreement between tracer-predicted and therapy-delivered tumor-absorbed dose was in the range 7%-21%. In summary, malignant lymphomas can have dramatic tumor regression within days of treatment, and advanced imaging methods allow for a highly patient-specific tumor-dosimetry calculation that accounts for this regression.

Hepatic absorbed radiation dosimetry during I-131 metaiodobenzylguanidine (MIBG) therapy for refractory neuroblastoma.

PURPOSE: To compare the prediction of therapeutic hepatic radiation-absorbed dose rates from tracer imaging plus a linearity assumption to estimation based on intra-therapy imaging in (131)I metaiodobenzylguanidine (MIBG) therapy of refractory neuroblastoma. MATERIALS AND METHODS: Conjugate-view images of the liver were obtained before therapy for seven patients at seven times after a tracer infusion of (131)I MIBG and at three times after the therapy infusion. Measured liver activities were converted to dose-rate estimates. Three statistical models of the rates assuming double exponential dependences on time were examined. One of the three models allowed for a multiplicative correction to the therapeutic late-phase dose-rate amplitude. Results from that model: (1) the tracer prediction of the late-phase absorbed-dose-rate amplitude was a factor of 1.75 times the intra-therapy-estimated value, and (2) the difference between tracer prediction of the radiation-absorbed dose and intra-therapy estimation of it was statistically significant, and (3) the liver radiation-absorbed dose did not reach 30 Gy. CONCLUSIONS: A statistical modeling analysis finds that the radiation-absorbed dose after therapy appears to be lower than that which is predicted from the linear scaling with administered activity of the tracer radiation-absorbed dose. Hepatocyte toxicity is the most likely reason but it is not high enough to produce clinically observable results.

Recovery of total I-131 activity within focal volumes using SPECT and 3D OSEM.

We experimentally investigated the SPECT recovery of I-131 activity in multiple spheres located simultaneously at different locations within a cylindrical phantom that had an elliptical cross section. The sphere volumes ranged from 209 cc down to 4.2 cc. A Prism 3000 camera and two types of parallel-hexagonal-hole collimation were employed: high energy (HE) and ultra high energy (UHE). Using appropriately-different 3D models of the point source response function for the two types of collimation, approximately the same recovery of activity could be achieved with either collimation by 3D OSEM reconstruction. The recovery coefficient was greater with no background activity in the phantom by 0.10, on average, compared to that with background. In the HE collimation case, the activity recovery was considerably better for all volumes using 3D OSEM reconstruction than it had been in the past using 1D SAGE reconstruction. Recovery-coefficient-based correction in a simulated patient case involving spherical tumours moderately improved the activity estimates (average error reduced from 14% to 9% for UHE collimation, and from 15% to 11% for HE collimation). For a test case with HE collimation, increasing the projection-image sampling density while decreasing the image voxel size increased the recovery coefficient by 0.075 on average, and, if used in a full set of calibration measurements of recovery coefficient versus volume, might lead to further improvement in accuracy for the patient case.

Accurate dosimetry in 131I radionuclide therapy using patient-specific, 3-dimensional methods for SPECT reconstruction and absorbed dose calculation.

UNLABELLED: (131)I radionuclide therapy studies have not shown a strong relationship between tumor absorbed dose and response, possibly due to inaccuracies in activity quantification and dose estimation. The goal of this work was to establish the accuracy of (131)I activity quantification and absorbed dose estimation when patient-specific, 3-dimensional (3D) methods are used for SPECT reconstruction and for absorbed dose calculation. METHODS: Clinically realistic voxel-phantom simulations were used in the evaluation of activity quantification and dosimetry. SPECT reconstruction was performed using an ordered-subsets expectation maximization (OSEM) algorithm with compensation for scatter, attenuation, and 3D detector response. Based on the SPECT image and a patient-specific density map derived from CT, 3D dosimetry was performed using a newly implemented Monte Carlo code. Dosimetry was evaluated by comparing mean absorbed dose estimates calculated directly from the defined phantom activity map with those calculated from the SPECT image of the phantom. Finally, the 3D methods were applied to a radioimmunotherapy patient, and the mean tumor absorbed dose from the new calculation was compared with that from conventional dosimetry obtained from conjugate-view imaging. RESULTS: Overall, the accuracy of the SPECT-based absorbed dose estimates in the phantom was >12% for targets down to 16 mL and up to 35% for the smallest 7-mL tumor. To improve accuracy in the smallest tumor, more OSEM iterations may be needed. The relative SD from multiple realizations was <3% for all targets except for the smallest tumor. For the patient, the mean tumor absorbed dose estimate from the new Monte Carlo calculation was 7% higher than that from conventional dosimetry. CONCLUSION: For target sizes down to 16 mL, highly accurate and precise dosimetry can be obtained with 3D methods for SPECT reconstruction and absorbed dose estimation. In the future, these methods can be applied to patients to potentially establish correlations between tumor regression and the absorbed dose statistics from 3D dosimetry.

Scatter modelling and compensation in emission tomography.

In nuclear medicine, clinical assessment and diagnosis are generally based on qualitative assessment of the distribution pattern of radiotracers used. In addition, emission tomography (SPECT and PET) imaging methods offer the possibility of quantitative assessment of tracer concentration in vivo to quantify relevant parameters in clinical and research settings, provided accurate correction for the physical degrading factors (e.g. attenuation, scatter, partial volume effects) hampering their quantitative accuracy are applied. This review addresses the problem of Compton scattering as the dominant photon interaction phenomenon in emission tomography and discusses its impact on both the quality of reconstructed clinical images and the accuracy of quantitative analysis. After a general introduction, there is a section in which scatter modelling in uniform and non-uniform media is described in detail. This is followed by an overview of scatter compensation techniques and evaluation strategies used for the assessment of these correction methods. In the process, emphasis is placed on the clinical impact of image degradation due to Compton scattering. This, in turn, stresses the need for implementation of more accurate algorithms in software supplied by scanner manufacturers, although the choice of a general-purpose algorithm or algorithms may be difficult.

Update on hybrid conjugate-view SPECT tumor dosimetry and response in 131I-tositumomab therapy of previously untreated lymphoma patients.

UNLABELLED: A study of the use of (131)I-labeled tositumomab, preceded by an unlabeled tositumomab predose, for therapy of 76 previously untreated non-Hodgkin's lymphoma patients has been completed at the University of Michigan. Fifty-two of the 76 treated patients were imaged once during therapy with SPECT to assist in dosimetric estimation. In this article, the patient's average tumor dose, estimated by a hybrid method using that SPECT, is compared with the same statistic estimated by pretherapy conjugate views. METHODS: The SPECT activity-quantification procedure used 3-dimensional CT-to-SPECT image registration. Daily pretherapy conjugate-view images provided the shape of the time-activity curve for the hybrid dose estimation. RESULTS: With the hybrid method, the mean of the patient's average tumor dose over 8 patients using only their axillary tumors (162 cGy) was very significantly lower (P < 0.0001) than the mean over 47 patients using only their evaluated chest, abdominal, and pelvic tumors (624 cGy) for unknown reasons. Excluding axillary tumors as a best case for prediction, there still was considerable overlap in the distribution of a patient's average tumor dose over 38 patients who went on to a complete response (CR) and that from 9 patients who went on to a partial response (PR) using either method. However, a high value of the patient's average tumor dose was correctly associated with a CR for 15 of 16 patients (94%) with hybrid SPECT and for 9 of 12 patients (75%) with conjugate views. Also, the mean of the patient's average tumor dose for the CR patients was larger than the mean for PR patients; the P value was 0.18 with hybrid SPECT and 0.25 with conjugate views. A multiple logistic regression analysis combining the dose, tumor burden, and level of lactate dehydrogenase as explanatory variables for response did not yield statistical significance with either method. CONCLUSION: Patients with evaluated tumors that receive the highest tumor radiation dose are most likely to achieve a CR. Dosimetry based on a combination of pretherapy conjugate views and intratherapy SPECT provides somewhat better correspondence between the patient's average tumor dose and his or her degree of response compared with dosimetry from pretherapy conjugate views alone. Statistical significance for the correspondence is not reached either with the dosimetric method or with either method in combination with the tumor burden and level of lactate dehydrogenase.

Volume reduction versus radiation dose for tumors in previously untreated lymphoma patients who received iodine-131 tositumomab therapy. Conjugate views compared with a hybrid method.

BACKGROUND: A Phase II study of previously untreated patients with malignant low grade follicular lymphoma given a combination of unlabeled tositumomab and tositumomab labeled with iodine-131 has recently been completed. The responses of these patients have been characterized, and for some of them tumor dosimetry during therapy has been estimated not only by pretherapy tracer conjugate views but also by a hybrid method. METHODS: Available patients were studied if they had had a pelvic or abdominal tumor evaluation by single photon emission computed tomography (SPECT) and achieved a partial response. A tumor outlined on the iodine-131 conjugate-view images was called a composite tumor. Its volume estimate came from multiple, not necessarily contiguous, regions of interest (ROI) on the pretherapy computed tomography (CT) scan. Its radiation dose was estimated from the weeklong series of pretherapy images and standard Medical Internal Radiation Dose methods. Computed tomography ROI were also grouped into smaller, contiguous volumes that defined individual tumors. Their radiation doses were estimated by the hybrid method. This method employed the activity measured for each individual tumor by a single intratherapy SPECT scan, as well as the tumor's volume, to individually normalize the composite time-activity curve as appropriate. The individual normalization factors then converted the composite radiation dose to radiation doses for individual tumors. Reduction in tumor volume was calculated for both composite and individual tumors at 12 weeks posttherapy. RESULTS: For 14 composite tumors in 10 patients, the median pretherapy volume was 170 cm(3). Application of a sigmoidal curve function to the plot of volume reduction versus radiation absorbed dose resulted in degeneration of the curve into a straight line with a negative slope. There was no statistical significance in the relationship (P = 0.73). For 43 individual tumors, the median pretherapy tumor volume was 26 cm(3). The plot of volume reduction versus dose was fairly well fit by a sigmoidal curve, and the relationship approached statistical significance (P = 0.06). The representation assigned 56% of the shrinkage to the effects of unlabeled tositumomab. For the subset of individual tumors with a pretherapy volume less than 10 cm(3) from 6 patients (n = 15), the relationship was significant (P = 0.03). The sigmoidal representation assigned only 12% of the shrinkage to unlabeled tositumomab, as contrasted with 72% for tumors with pretherapy volume greater than 10 cm(3). CONCLUSIONS: For patients who attained a partial response, analysis of individual tumors by a hybrid dosimetric method led to a dependence between volume reduction at 12 weeks and radiation dose that tended to be significant. The same was not true with dosimetry of composite tumors based on pretherapy conjugate views alone. It appeared that volume reductions from both unlabeled antibody and radiation dose were important in tositumomab therapy of lymphoma patients, with unlabeled antibody relatively more important for larger tumors.

A parallel Monte Carlo code for planar and SPECT imaging: implementation, verification and applications in (131)I SPECT.

This paper reports the implementation of the SIMIND Monte Carlo code on an IBM SP2 distributed memory parallel computer. Basic aspects of running Monte Carlo particle transport calculations on parallel architectures are described. Our parallelization is based on equally partitioning photons among the processors and uses the Message Passing Interface (MPI) library for interprocessor communication and the Scalable Parallel Random Number Generator (SPRNG) to generate uncorrelated random number streams. These parallelization techniques are also applicable to other distributed memory architectures. A linear increase in computing speed with the number of processors is demonstrated for up to 32 processors. This speed-up is especially significant in Single Photon Emission Computed Tomography (SPECT) simulations involving higher energy photon emitters, where explicit modeling of the phantom and collimator is required. For (131)I, the accuracy of the parallel code is demonstrated by comparing simulated and experimental SPECT images from a heart/thorax phantom. Clinically realistic SPECT simulations using the voxel-man phantom are carried out to assess scatter and attenuation correction.