Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy.
ABSTRACT Purpose: Peptide receptor radionuclide therapy (PRRT) delivers high absorbed doses to kidneys and may lead to permanent nephropathy. Reliable dosimetry of kidneys is thus critical for safe and effective PRRT. The aim of this work was to assess the feasibility of planning PRRT based on 3D radiobiological dosimetry (3D-RD) in order to optimize both the amount of activity to administer and the fractionation scheme, while limiting the absorbed dose and the biological effective dose (BED) to the renal cortex.Methods: Planar and SPECT data were available for a patient examined with (111)In-DTPA-octreotide at 0.5 (planar only), 4, 24, and 48 h post-injection. Absorbed dose and BED distributions were calculated for common therapeutic radionuclides, i.e., (111)In, (90)Y and (177)Lu, using the 3D-RD methodology. Dose-volume histograms were computed and mean absorbed doses to kidneys, renal cortices, and medullae were compared with results obtained using the MIRD schema (S-values) with the multiregion kidney dosimetry model. Two different treatment planning approaches based on (1) the fixed absorbed dose to the cortex and (2) the fixed BED to the cortex were then considered to optimize the activity to administer by varying the number of fractions.Results: Mean absorbed doses calculated with 3D-RD were in good agreement with those obtained with S-value-based SPECT dosimetry for (90)Y and (177)Lu. Nevertheless, for (111)In, differences of 14% and 22% were found for the whole kidneys and the cortex, respectively. Moreover, the authors found that planar-based dosimetry systematically underestimates the absorbed dose in comparison with SPECT-based methods, up to 32%. Regarding the 3D-RD-based treatment planning using a fixed BED constraint to the renal cortex, the optimal number of fractions was found to be 3 or 4, depending on the radionuclide administered and the value of the fixed BED. Cumulative activities obtained using the proposed simulated treatment planning are compatible with real activities administered to patients in PRRT.Conclusions: The 3D-RD treatment planning approach based on the fixed BED was found to be the method of choice for clinical implementation in PRRT by providing realistic activity to administer and number of cycles. While dividing the activity in several cycles is important to reduce renal toxicity, the clinical outcome of fractionated PRRT should be investigated in the future.
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ABSTRACT: Purpose: Three-dimensional (3D) dosimetry has the potential to provide better prediction of response of normal tissues and tumors and is based on 3D estimates of the activity distribution in the patient obtained from emission tomography. Dose-volume histograms (DVHs) are an important summary measure of 3D dosimetry and a widely used tool for treatment planning in radiation therapy. Accurate estimates of the radioactivity distribution in space and time are desirable for accurate 3D dosimetry. The purpose of this work was to develop and demonstrate the potential of penalized SPECT image reconstruction methods to improve DVHs estimates obtained from 3D dosimetry methods. Methods: We developed penalized image reconstruction methods, using maximum a posteriori (MAP) formalism, which intrinsically incorporate regularization in order to control noise and, unlike linear filters, are designed to retain sharp edges. Two priors were studied: one is a 3D hyperbolic prior, termed single-time MAP (STMAP), and the second is a 4D hyperbolic prior, termed cross-time MAP (CTMAP), using both the spatial and temporal information to control noise. The CTMAP method assumed perfect registration between the estimated activity distributions and projection datasets from the different time points. Accelerated and convergent algorithms were derived and implemented. A modified NCAT phantom with a multi-compartment kidney model and organ activities and parameters derived from clinical studies were used in a Monte Carlo simulation study to evaluate the methods. Cumulative dose-rate volume histograms (CDRVHs) and cumulative DVHs (CDVHs) obtained from the phantom and from SPECT images reconstructed with both the penalized algorithms and OS-EM were calculated and compared both qualitatively and quantitatively. The STMAP was applied to patient data and CDRVHs obtained with STMAP and OS-EM were compared qualitatively. Results: The results showed that the penalized algorithms substantially improved the CDRVH and CDVH estimates for large organs such as the liver compared to optimally post-filtered OS-EM. For example, the mean squared errors (MSEs) of the CDRVHs for the liver at 5 hours post-injection obtained with CTMAP and STMAP were about 15% and 17%, respectively, of the MSEs obtained with optimally-filtered OS-EM. For the CDVH estimates, the MSEs obtained with CTMAP and STMAP were about 16% and 19%, respectively, of the MSEs from OS-EM. For the kidneys and renal cortices, larger residual errors were observed for all the algorithms, likely due to partial volume effects (PVEs). The STMAP method showed promising qualitative results when applied to patient data. Conclusions: Penalized image reconstruction methods were developed and evaluated through a simulation study. The study showed that the MAP algorithms substantially improved CDVH estimates for large organs such as the liver compared to optimally post-filtered OS-EM reconstructions. For small organs with fine structural detail such as the kidneys, a large residual error was observed for both MAP algorithms and OS-EM. While CTMAP provided marginally better MSEs than STMAP, given the extra effort needed to handle misregistration of images at different time points in the algorithm and the potential impact of residual misregistration, 3D regularization methods, such as that used in STMAP, appear to be a more practical choice.Medical Physics 11/2014; 41(11):112507. · 3.01 Impact Factor
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ABSTRACT: Peptide receptor radionuclide therapy (PRRT) has been shown to be an effective treatment for neuroendocrine tumors (NETs) if curative surgery is not an option. A majority of NETs abundantly express somatostatin receptors. Consequently, following administration of somatostatin (SST) analogs labeled with γ-emitting radionuclides, these tumors can be imaged for diagnosis, staging or follow-up purposes. Furthermore, when β-emitting radionuclides are used, radiolabeled peptides (radiopeptides) can also be used for the treatment for NET patients. Even though excellent results have been achieved with PRRT, complete responses are still rare, which means that there is room for improvement. In this review, we highlight some of the directions currently under investigation in pilot clinical studies or in preclinical development to achieve this goal. Although randomized clinical trials are still lacking, early studies have shown that tumor response might be improved by application of other radionuclides, such as α-emitters or radionuclide combinations, or by adjustment of radiopeptide administration routes. Individualized dosimetry and better insight into tumor and normal organ radiation doses may allow adjustment of the amount of administered activity per cycle or the number of treatment cycles, resulting in more personalized treatment schedules. Other options include the application of novel (radiolabeled) SST analogs with improved tumor uptake and radionuclide retention time, or a combination of PRRT with other systemic therapies, such as chemotherapy or treatment with radio sensitizers. Though promising directions appear to bring improvements of PRRT within reach, additional research (including randomized clinical trials) is needed to achieve such improvements.Clinical and translational imaging : reviews in nuclear medicine and molecular imaging. 02/2014; 2(1):55-66.
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ABSTRACT: Radiopharmaceutical therapy (RPT) involves the use of radionuclides that are either conjugated to tumor-targeting agents (e.g., nanoscale constructs, antibodies, peptides, and small molecules) or concentrated in tissue through natural physiological mechanisms that occur predominantly in neoplastic or otherwise targeted cells (e.g., Graves disease). The ability to collect pharmacokinetic data by imaging and use this to perform dosimetry calculations for treatment planning distinguishes RPT from other systemic treatment modalities such as chemotherapy, wherein imaging is not generally used. Treatment planning has not been widely adopted, in part, because early attempts to relate dosimetry to outcome were not successful. This was partially because a dosimetry methodology appropriate to risk evaluation rather than efficacy and toxicity was being applied to RPT. The weakest links in both diagnostic and therapeutic dosimetry are the accuracy of the input and the reliability of the radiobiological models used to convert dosimetric data to the relevant biologic end points. Dosimetry for RPT places a greater demand on both of these weak links. To date, most dosimetric studies have been retrospective, with a focus on tumor dose-response correlations rather than prospective treatment planning. In this regard, transarterial radioembolization also known as intra-arterial radiation therapy, which uses radiolabeled ((90)Y) microspheres of glass or resin to treat lesions in the liver holds much promise for more widespread dosimetric treatment planning. The recent interest in RPT with alpha-particle emitters has highlighted the need to adopt a dosimetry methodology that specifically accounts for the unique aspects of alpha particles. The short range of alpha-particle emitters means that in cases in which the distribution of activity is localized to specific functional components or cell types of an organ, the absorbed dose will be equally localized and dosimetric calculations on the scale of organs or even voxels (~5mm) are no longer sufficient. This limitation may be overcome by using preclinical models to implement macromodeling to micromodeling. In contrast to chemotherapy, RPT offers the possibility of evaluating radiopharmaceutical distributions, calculating tumor and normal tissue absorbed doses, and devising a treatment plan that is optimal for a specific patient or specific group of patients.Seminars in nuclear medicine 05/2014; 44(3):172-178. · 3.96 Impact Factor