Antigoni Divoli

Effect of Patient Morphology on Dosimetric Calculations for Internal Irradiation as Assessed by Comparisons of Monte Carlo Versus Conventional Methodologies

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.

Estimation of random coincidences from the prompt PET data

Currently the most widely implemented method for estimating the random events present in PET prompt data is the delayed-coincidence-channel method. The delayed randoms are usually subtracted from the prompts. However, the acquired randoms suffer from poor statistics and post processing variance reduction techniques are often used prior to the subtraction. We have developed a new method of estimating the randoms from the PET prompt data acquired in list or sinogram mode (LM or SM respectively). In both cases random events were obtained by swapping the detection coordinates of prompt events. The statistics of the estimated randoms could virtually be unlimited. For LM data the process was straightforward and easily implemented, but for SM data a multi-step algorithm was developed.

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.

Normalisation of emission and transmission data taken with a large-area positron camera, PETRRA

Prior to reconstruction, emission and transmission data must be normalised to account for crystal non-uniformities and for geometric effects. The method described in this work for emission scans is based on the inversion of flood images that are acquired with ether a point or a plane source. The correction is applied in the event by backprojection (BP) of the list mode data obtained with PETRRA, a novel PET scanner that comprises two large area detectors. For transmission images linear interpolation was used unsuccessfully to predict values of the missing areas of the detectors that correspond to gaps between the crystals and the crystal support frame. Iterative reconstruction methods did not solve the problem either. Simulation data showed that more than one source position could remove circular artifacts in transmission imaging.

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

Abstract 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.

Implementation of spiral PET on cameras with rotating planar detectors

Whole-body PET scanning is achieved by using couch movement to extend the field of view beyond the axial length of the detectors. For PET cameras with rotating planar detectors whole-body scanning can be achieved via spiral PET i.e. by simultaneous and continuous couch translation and gantry rotation. Higher SNRs are obtained when continuous couch motion is used compared with the more conventional step-and-shoot methods of whole-body PET acquisition. The large axial extent of PET cameras with rotating planar detectors and their inherent 3D geometry make these cameras ideally suited to continuous sampling and a spiral mode of acquisition for wholebody imaging. Hardware and software have been developed for list-mode spiral PET acquisition using the PETRRA camera. Image reconstruction is based on backprojection and filtering techniques. Previous optimization of the image reconstruction method and parameters using the MUP-PET camera has been adapted to account for the different geometries of the two cameras. To achieve accurate quantification, the data need to be corrected for non-uniform sampling (by application of both rotational and longitudinal weights), as well as for camera nonuniformity, randoms, deadtime, attenuation and scatter. High-quality whole-body images have been produced of phantom data acquired with short scanning times under ideal conditions of minimal scatter and randoms. Image quantification is still to be achieved on PETRRA via implementation of corrections for scatter and randoms. Spiral PET, as implemented on PETRRA, could be applied to gamma-camera PET systems, provided they offer continuous gantry rotation, couch translation and list-mode data acquisition.

Optimisation of source geometry for flood images to be used for nonuniformity corrections on large area detectors

Prior to reconstruction, emission data must be normalised to account for crystal nonuniformities and for geometric effects. The method adopted for normalisation of data acquired with the novel positron camera PETRRA is a direct method based on the inversion of a pair of flood images. In this work sources of several geometries for the flood acquisitions were tested on tomographic data. The different source geometries were: a /sup 68/Ge point source in static and tomographic mode, a 2D plane source filled with /sup 18/F, and a 3D uniform cylinder filled with /sup 18/F.

Backprojection-space 3D scatter correction for the PETRRA positron camera

Positron volume images have been produced by the new large-area positron camera PETRRA directly from list-mode data acquisition then reconstruction using backprojection then filter methods (BPF). These images have been corrected for scatter and attenuation using backprojection space methods. Two methods have been developed to provide scatter distributions. The first method uses a spatially-invariant scatter response function derived from measured point spread functions in a water-filled phantom. The second uses the scatter distributions measured at various points in the same phantom to allow for the spatial variance of the scatter. The correction methods have been tested using a uniformly-filled radioactive elliptical phantom (major and minor axes of 29.5 cm and 19.6 cm). Preliminary results show that both methods can improve the quantitative nature of the reconstructed images but that the use of spatially variant scatter distribution is superior. The methods could be applied to any large-area, rotating positron camera system which acquires data in list mode.

Reply to 'Single high dose versus repeated bone-targeted radionuclide therapy'

We would like to thank Liepe [1] for his interest in our recent article and giving us the opportunity to further expand upon some additional aspects of the study [2]. The data used for the present study [2] belong to two National Institute of Health (NIH) funded activity escalation phase I [3] and fixed administered activity phase II [4] clinical trials. A total of 57 patients were recruited between 1996 and 2003, before availability of Ra-dichloride or chemotherapy agents such as docetaxel and/or abiraterone. The aims of these trials were to investigate the feasibility and toxicity profile of high administered activities of Re-HEDP and autologous peripheral blood stem cell transplantation (PBSCT) in patients with castration-resistant prostate cancer metastatic to bone (mCRPC). The results of these studies were previously published [3, 4]. Amaximum tolerated activity of 5 GBq of ReHEDP was determined in the phase I trial, with a statistically significant prostate-specific antigen (PSA) improved response in patients receiving activities above 3.5 GBq. The phase II study demonstrated the safe delivery of a fixed 5 GBq of Re-HEDP and PBSCT in a group of 38 patients with mCRPC. The aim of our recent publication was to use the long-term survival and imaging data available to study the potential of imaging and dosimetry to predict response and outcome. Our study did not intend to discuss whether high administered activities and PBSCTare the best treatment strategy for patients with mCRPC [2]. Liepe raises concerns about the lack of a sample size calculation for the overall survival (OS) analysis according to administered activity levels, the capture of patient follow-up, and the inclusion of patients treated with Ra-dichloride or docetaxel. Our post hoc analysis showed a statistically significant difference in survival between the lowand high-activity groups and a sample size calculation was not included, as this was not an end-point to the original trials and not needed for this type of analysis. As stated in our publication [2], followup time was used for OS analysis as the time interval between administration of Re-HEDP and death, which was documented for 50 of the 57 patients. Seven patients were censored at the last point of contact, or at the time they received a treatment prolonging survival. Our results showed a statistically significant difference in overall survival for both groups, with a median OS advantage of 13 months, which could not be explained by differences in baseline prognostic factors. Unfortunately, imaging was not available for all patients, so it was not possible to determine whether patients treated with > 3.5 GBq received higher absorbed doses, which could have affected survival. Nonetheless, this result was considered of potential interest for future studies, particularly in light of newly emerging radiopharmaceuticals also showing a prolonged survival for higher administered activities [5]. This Editorial Commentary refers to the article http://dx.doi.org/10.1007/ s00259-017-3815-0.

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.