Phase I/II trials of 186Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival.

PURPOSE: To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit. METHODS: Clinical data from 57 patients who received 2.5-5.1 GBq of 186Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan-Meier curves, log-rank tests, Cox's proportional hazards model and Pearson's correlation coefficients were used for overall survival (OS) and correlation analyses. RESULTS: A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10-0.58, P = 0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of 186Re-HEDP (P = 0.03) and patient mean absorbed dose (P = 0.01), whilst only the disease volume remained significant in a multivariable analysis (P = 0.004). CONCLUSION: This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated with survival. This study shows the importance of patient stratification to establish absorbed dose-response correlations and indicates the potential to individualise treatment of bone metastases with radiopharmaceuticals according to patient-specific imaging and dosimetry.

Effect of patient morphology on dosimetric calculations for internal irradiation as assessed by comparisons of Monte Carlo versus conventional methodologies.

UNLABELLED: Dosimetric calculations are performed with an increasing frequency before or after treatment in targeted radionuclide therapy, as well as for radiation protection purposes in diagnostic nuclear medicine. According to the MIRD committee formalism, the mean absorbed dose to a target is given by the product of the cumulated activity and a dose-conversion factor, known as the S factor. Standard S factors have been published for mathematic phantoms and for unit-density spheres. The accuracy of the results from the use of these S factors is questionable, because patient morphology can vary significantly. The aim of this work was to investigate differences between patient-specific dosimetric results obtained using Monte Carlo methodology and results obtained using S factors calculated on standard models. METHODS: The CT images of 9 patients, who ranged in size, were used. Patient-specific S factors for 131I were calculated with the MCNPX2.5.0 Monte Carlo code using a tool for personalized internal dose assessment, OEDIPE; standard S factors from OLINDA/EXM were compared against the patient-specific S factors. Furthermore, realistic biodistributions and cumulated activities for normal organs and tumors were used, and mean organ- and tumor-absorbed doses calculated with OEDIPE and OLINDA/EXM were compared. RESULTS: The ratio of the standard and the patient-specific S factors were between 0.49 and 1.84 for a target distant from the source for 4 organs and 2 tumors studied as source and targets. For the case of self-irradiation, the equivalent ratio ranged between 0.45 and 2.47 and between 1.00 and 1.06 when mass correction was applied. Differences in mean absorbed doses were as high as 140% when realistic cumulated activity values were used. These values decreased to less than 26% in all cases studied when mass correction was applied to the self-irradiation given by OLINDA/EXM. CONCLUSION: Standard S factors can yield mean absorbed doses for normal organs or tumors with a reasonable accuracy (26% for the cases studied) as compared with absorbed doses calculated with Monte Carlo, provided that they have been corrected for mass.

Bone lesion absorbed dose profiles in patients with metastatic prostate cancer treated with molecular radiotherapy.

OBJECTIVE: The aim of this study was to calculate the range of absorbed doses that could potentially be delivered by a variety of radiopharmaceuticals and typical fixed administered activities used for bone pain palliation in a cohort of patients with metastatic castration-resistant prostate cancer (mCRPC). The methodology for the extrapolation of the biodistribution, pharmacokinetics and absorbed doses from a given to an alternative radiopharmaceutical is presented. METHODS: Sequential single photon emission CT images from 22 patients treated with 5 GBq of 186Re-HEDP were used to extrapolate the time-activity curves for various radiopharmaceuticals. Cumulated activity distributions for the delivered and extrapolated treatment plans were converted into absorbed dose distributions using the convolution dosimetry method. The lesion absorbed doses obtained for the different treatments were compared using the patient population distributions and cumulative dose-volume histograms. RESULTS: The median lesion absorbed doses across the patient cohort ranged from 2.7 Gy (range: 0.6-11.8 Gy) for 1100 MBq of 166Ho-DOTMP to 21.8 Gy (range: 4.5-117.6 Gy) for 150 MBq of 89Sr-dichloride. 32P-Na3PO4, 153Sm-EDTMP, 166Ho-DOTMP, 177Lu-EDTMP and 188Re-HEDP would have delivered 41, 32, 85, 20 and 64% lower absorbed doses, for the typical administered activities as compared to 186Re-HEDP, respectively, whilst 89Sr-dichloride would have delivered 25% higher absorbed doses. CONCLUSION: For the patient cohort studied, a wide range of absorbed doses would have been delivered for typical administration protocols in mCRPC. The methodology presented has potential use for emerging theragnostic agents. Advances in knowledge: The same patient cohort can receive a range of lesion absorbed doses from typical molecular radiotherapy treatments for patients with metastatic prostate cancer, highlighting the need to establish absorbed dose response relationships and to treat patients according to absorbed dose instead of using fixed administered activities.

The importance of the accuracy of image registration of SPECT images for 3D targeted radionuclide therapy dosimetry.

In this paper, the importance of the accuracy of image registration of time-sequential SPECT images for 3D targeted radionuclide therapy dosimetry is studied. Image registration of a series of SPECT scans is required to allow the computation of the 3D absorbed dose distribution for both tumour sites and normal organs. Three simulated 4D datasets, based on patient therapy studies, were generated to allow the effect of mis-registration on the absorbed dose distribution to be investigated. The tumour sites studied range in size, shape and position, relative to the centre of the 3D SPECT scan. Randomly generated transformations along the x-, y- and z-axes and rotations around the z-axis were employed and the maximum and average absorbed dose distribution statistics, for the tumour sites present, were computed. It was shown that even small mis-registrations, translation of less than 9 mm and rotation of less than 5 degrees might cause differences in the absorbed dose statistics of up to 90%, especially when the size of the tumour is comparable to the induced mis-registration or when the tumour is situated close to the edge of the 3D dataset.

A generalized 4D image registration scheme for targeted radionuclide therapy dosimetry.

An iterative, generalized four-dimensional (4D) method is presented in this paper that allows simultaneous registration of a series of single-photon emission computed tomography (SPECT) scans acquired in the course of a radionuclide therapy or pretherapy tracer study. The method combines temporal information with voxel-based similarity criteria to carry out simultaneous registration of the SPECT scans. A polynomial function was fitted to the maximum counts of each tumor site over the 4D study. Each tumor site was normalized to its maximum on the reference scan, and a template 4D dataset was generated, employing the polynomial fitting and the normalization map. Then, each 3D scan was registered to the corresponding simulated scan, using a 3D similarity criterion. The correlation coefficient (CC), the mutual information (MI), and the sum-of-absolute differences (SAD) similarity criteria were employed. Simulated data, based on a head-neck (131)I-MIBG study, were used to compare the proposed method for 4D registration with sequential 3D registration. Sequential 3D registration resulted in residual registration errors of 3.5 +/- 2.5, 3.2 +/- 2.0, and 7.0 +/- 3.5 mm for the CC, MI, and SAD criteria respectively, whereas the corresponding 4D method gave errors of 2.4 +/- 1.6, 1.9 +/- 1.1, and 5.3 +/- 2.9 mm for the CC, MI, and SAD criteria, respectively. The 4D method was applied to (186)Re HEDP SPECT patient studies and registration was verified by a dual-cursor display tool.

Tumor dosimetry on SPECT (186)Re-HEDP scans: variations in the results from the reconstruction methods used.

The aim of this work was to estimate tumor-absorbed doses delivered from the administration of fixed activities of (186)Re-HEDP for the treatment of bone metastases from prostate cancer. The variations and reproducibility in the estimated absorbed dose owing to the reconstruction algorithm used (OSEM vs. FBP) were also analysed. For this aim, correction methods for scatter and attenuation were kept identical, whereas the same calibration data and thresholding techniques were used to obtain quantification. This study was carried out in spinal and pelvic lesions of 7 patients. For comparison, the absorbed doses, based upon the maximum and the mean voxel count, were calculated, resulting in the absorbed dose (maximum): 60 Gy (sigma = 30 Gy) and 33 Gy (sigma = 15 Gy) for OSEM and FBP, respectively, and absorbed dose (mean): 26 Gy (sigma = 12 Gy) and 17 Gy (sigma = 7 Gy) with OSEM and FBP, respectively. We concluded that the administration of fixed activity resulted in a range of absorbed doses, and we showed that, despite using the same approach, the choice of the reconstruction algorithm can result in differences higher than 50% in the estimated tumor-absorbed doses. In conclusion, the need for a standardization of the methodology used for the calculations is emphasized by this work, especially when comparisons between patients and different centers are of interest.

A radiobiological model of metastatic burden reduction for molecular radiotherapy: application to patients with bone metastases.

Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: 83-105 Gy), whilst a median of 183 Gy (interquartile range: 107-247 Gy) was found necessary to eradicate all metastases in a given patient. The absorbed dose required to eradicate all the lesions was strongly correlated with the variability of the absorbed doses delivered to multiple lesions in a given patient (r = 0.98, P < 0.0001). The metastatic burden reduction curves showed a potential large reduction in metastatic burden for a small increase in absorbed dose in 91% of patients. The results indicate the range of absorbed doses required to potentially obtain a significant survival benefit. The metastatic burden reduction method provides a simple tool that could be used in routine clinical practice for patient selection and to indicate the required administered activity to achieve a predicted patient mean absorbed dose and reduction in metastatic tumour burden.

Abdo-Man: a 3D-printed anthropomorphic phantom for validating quantitative SIRT.

BACKGROUND: The use of selective internal radiation therapy (SIRT) is rapidly increasing, and the need for quantification and dosimetry is becoming more widespread to facilitate treatment planning and verification. The aim of this project was to develop an anthropomorphic phantom that can be used as a validation tool for post-SIRT imaging and its application to dosimetry. METHOD: The phantom design was based on anatomical data obtained from a T1-weighted volume-interpolated breath-hold examination (VIBE) on a Siemens Aera 1.5 T MRI scanner. The liver, lungs and abdominal trunk were segmented using the Hermes image processing workstation. Organ volumes were then uploaded to the Delft Visualization and Image processing Development Environment for smoothing and surface rendering. Triangular meshes defining the iso-surfaces were saved as stereo lithography (STL) files and imported into the Autodesk® Meshmixer software. Organ volumes were subtracted from the abdomen and a removable base designed to allow access to the liver cavity. Connection points for placing lesion inserts and filling holes were also included. The phantom was manufactured using a Stratasys Connex3 PolyJet 3D printer. The printer uses stereolithography technology combined with ink jet printing. Print material is a solid acrylic plastic, with similar properties to polymethylmethacrylate (PMMA). RESULTS: Measured Hounsfield units and calculated attenuation coefficients of the material were shown to also be similar to PMMA. Total print time for the phantom was approximately 5 days. Initial scans of the phantom have been performed with Y-90 bremsstrahlung SPECT/CT, Y-90 PET/CT and Tc-99m SPECT/CT. The CT component of these images compared well with the original anatomical reference, and measurements of volume agreed to within 9 %. Quantitative analysis of the phantom was performed using all three imaging techniques. Lesion and normal liver absorbed doses were calculated from the quantitative images in three dimensions using the local deposition method. CONCLUSIONS: 3D printing is a flexible and cost-efficient technology for manufacture of anthropomorphic phantom. Application of such phantoms will enable quantitative imaging and dosimetry methodologies to be evaluated, which with optimisation could help improve outcome for patients.

The potential use of 99mTc-MDP bone scans to plan high-activity 186Re-HEDP targeted therapy of bony metastases from prostate cancer.

Patients with skeletal metastases from hormone-refractory prostate cancer have shown variable responses to high-activity therapy with (186)Re-HEDP and peripheral stem cell support. In this paper, we report on the use of a novel technique to compare sequential planar images acquired post-(186)Re-HEDP therapy administration with pretherapy diagnostic (99m)Tc-MDP scans, to evaluate the turnover of the radiopharmaceutical in normal and abnormal bone. It was found that the activity in normal (i.e., disease-free) segments of the spine demonstrates a faster effective decay than that of the metastases, with the latter showing only physical decay. This study showed, for the first time, a detailed correlation in the behavior of the (99m)Tc-MDP and (186)Re-HEDP images, encouraging the possibility of using the pretherapy 99mTc-MDP scan for estimations of absorbed doses to be delivered by prescribed activities of (186)Re-HEDP.

Whole-body dosimetry for targeted radionuclide therapy using spectral analysis.

The whole-body dose (WBD) is routinely calculated for targeted radionuclide therapy (TRT). The aim of this work was to investigate the feasibility of using spectral analysis (SA) for the automatic delineation of decay phases, and consequently, the calculation of the WBD given a whole-body (WB) time-activity curve (TAC). SA characterizes the TAC as an arbitrary sum of exponential functions determined by fitting the data with a non-negative least-squares (NNLS) algorithm. The cumulated activity (CA) is calculated analytically as the integral of the fitted curve while the number of phases describing the kinetics of the radiopharmaceutical and the half-lives of the phases can be determined from the spectrum. The uncertainty associated with the estimation of the WBD can be obtained using bootstrap techniques. SA was applied to WB TACs from (186)Re-HEDP and (131)I-mIBG therapies. The results were compared to results obtained using a semiempirical method and showed good agreement in the calculated WBDs. Bootstrapping with resampling on a subset of patients from the two therapies showed much larger coefficient-ofvariation (CV) for the (186)Re-HEDP TACs than for the (131)I-mIBG therapies. We concluded that SA provides a fast, accurate, and reproducible method to obtain WBDs and accurate estimates of the parameters describing the radiotracer kinetics. The method could be extended to other dosimetric applications.