A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR).

BACKGROUND: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. METHODS: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). DISCUSSION: Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06059014.

Phase II study of 131 I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP.

PURPOSE: We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of 131 I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL). METHODS: Patients received 131 I-mIBG on day 1, with intravenous topotecan daily on days 1-5. A second activity of 131 I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21-25. Peripheral blood stem cells were infused on day 31. RESULTS: Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2-20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1-26). Median number of prior lines of treatment was 3 (1-7). Objective response rate was 13% (95% confidence interval [CI]: 4-31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6-32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years). CONCLUSION: MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.

A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients.

BACKGROUND: Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10, overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions. METHODS: Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90Y-OTSA-101 for radionuclide therapy. RESULTS: From January 2012 to June 2015, 20 pts. (median age 43 years [21-67]) with advanced SS were enrolled. Even though 111In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient. CONCLUSIONS: Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index. TRIAL REGISTRATION: The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.

A review of 177Lu dosimetry workflows: how to reduce the imaging workloads?

177 Lu radiopharmaceutical therapy is a standardized systemic treatment, with a typical dose of 7.4 GBq per injection, but its response varies from patient to patient. Dosimetry provides the opportunity to personalize treatment, but it requires multiple post-injection images to monitor the radiopharmaceutical's biodistribution over time. This imposes an additional imaging burden on centers with limited resources. This review explores methods to lessen this burden by optimizing acquisition types and minimizing the number and duration of imaging sessions. After summarizing the different steps of dosimetry and providing examples of dosimetric workflows for 177 Lu -DOTATATE and 177 Lu -PSMA, we examine dosimetric workflows based on a reduced number of acquisitions, or even just one. We provide a non-exhaustive description of simplified methods and their assumptions, as well as their limitations. Next, we detail the specificities of each normal tissue and tumors, before reviewing dose-response relationships in the literature. In conclusion, we will discuss the current limitations of dosimetric workflows and propose avenues for improvement.

360° CZT-SPECT/CT cameras: 99mTc- and 177Lu-phantom-based evaluation under clinical conditions.

PURPOSE: For the first time, three currently available 360° CZT-SPECT/CT cameras were compared under clinical conditions using phantom-based measurements. METHODS: A 99mTc- and a 177Lu-customized NEMA IEC body phantom were imaged with three different cameras, StarGuide (GE Healthcare), VERITON-CT versions 200 (V200) and 400 (V400) (Spectrum Dynamics Medical) under the same clinical conditions. Energy resolution and volumetric sensitivity were evaluated from energy spectra. Vendors provided the best reconstruction parameters dedicated to visualization and/or quantification, based on their respective software developments. For both 99mTc- and 177Lu-phantoms, noise level, quantification accuracy, and recovery coefficient (RC) were performed with 3DSlicer. Image quality metrics from an approach called "task-based" were computed with iQMetrix-CT on 99mTc visual reconstructions to assess, through spatial frequencies, noise texture in the background (NPS) and contrast restitution of a hot insert (TTF). Spatial resolution indices were calculated from frequencies corresponding to TTF10% and TTF50%. RESULTS: Despite the higher sensitivity of VERITON cameras and the enhanced energy resolution of the V400 (3.2% at 140 keV, 5.2% at 113 keV, and 3.6% at 208 keV), StarGuide presents comparable image quality. This highlights the need to differentiate sensitivity from count quality, which is influenced by hardware design (collimator, detector block) and conditions image quality as well as the reconstruction process (algorithms, scatter correction, noise regulation). For 99mTc imaging, the quantitative image optimization approach based on RCmean for StarGuide versus RCmax for V200 and V400 systems (RCmean/RCmax: 0.9/1.8; 0.5/0.9; 0.5/0.9 respectively-Ø37 mm). SRTB10/50 showed nearly equivalent spatial resolution performances across the different reconstructed images. For 177Lu imaging, the 113 keV imaging of the V200 and V400 systems demonstrated strong performances in both image quality and quantification, while StarGuide and V400 systems offer even better potential due to their ability to exploit signals from both the 113 and 208 keV peaks. 177Lu quantification was optimized according to RCmax for all cameras and reconstructions (1.07 ± 0.09-Ø37 mm). CONCLUSIONS: The three cameras have equivalent potential for 99mTc imaging, while StarGuide and V400 have demonstrated higher potential for 177Lu. Dedicated visual or quantitative reconstructions offer better specific performances compared to the unified visual/quantitative reconstruction. The task-based approach appears to be promising for in-depth comparison of images in the context of system characterization/comparison and protocol optimization.

Implementation of dosimetry for molecular radiotherapy; results from a European survey.

PURPOSE: The use of molecular radiotherapy (MRT) has been rapidly evolving over the last years. The aim of this study was to assess the current implementation of dosimetry for MRTs in Europe. METHODS: A web-based questionnaire was open for treating centres between April and June 2022, and focused on 2020-2022. Questions addressed the application of 16 different MRTs, the availability and involvement of medical physicists, software used, quality assurance, as well as the target regions for dosimetry, whether treatment planning and/or verification were performed, and the dosimetric methods used. RESULTS: A total of 173 responses suitable for analysis was received from centres performing MRT, geographically distributed over 27 European countries. Of these, 146 centres (84 %) indicated to perform some form of dosimetry, and 97 % of these centres had a medical physicist available and almost always involved in dosimetry. The most common MRTs were 131I-based treatments for thyroid diseases and thyroid cancer, and [223Ra]RaCl2 for bone metastases. The implementation of dosimetry varied widely between therapies, from almost all centres performing dosimetry-based planning for microsphere treatments to none for some of the less common treatments (like 32P sodium-phosphate for myeloproliferative disease and [89Sr]SrCl2 for bone metastases). CONCLUSIONS: Over the last years, implementation of dosimetry, both for pre-therapeutic treatment planning and post-therapy absorbed dose verification, increased for several treatments, especially for microsphere treatments. For other treatments that have moved from research to clinical routine, the use of dosimetry decreased in recent years. However, there are still large differences both across and within countries.

Unintentional Intra-arterial Injection of 177Lu-PSMA-1 in a Patient With a Peritoneal Carcinosis Secondary to a Metastatic Prostate Cancer.

ABSTRACT: We report the case of an 81-year-old man presenting with peritoneal carcinosis secondary to a metastatic castrate-resistant prostate cancer addressed for 177Lu-PSMA-1 therapy. During the second cycle, a diffuse uptake in his left forearm was observed on the 1-hour postinjection scintigraphy, typical for an accidental intra-arterial injection. Less than 24 hours postinjection, a full removal of the intra-arterial injection was observed in the man, without any pain or symptoms. Moreover, the man demonstrated an 85% PSA reduction and a CT OR following the RECIST 1.1 criteria after 3 cycles.

Dosimetric impact of 3D motion-compensated SPECT reconstruction for SIRT planning.

BACKGROUND: In selective internal radiation therapy, 99mTc SPECT images are used to optimize patient treatment planning, but they are affected by respiratory motion. In this study, we evaluated on patient data the dosimetric impact of motion-compensated SPECT reconstruction on several volumes of interest (VOI), on the tumor-to-normal liver (TN) ratio and on the activity to be injected. METHODS: Twenty-nine patients with liver cancer or hepatic metastases treated by radioembolization were included in this study. The biodistribution of 90Y is assumed to be the same as that of 99mTc when predictive dosimetry is implemented. A total of 31 99mTc SPECT images were acquired and reconstructed with two methods: conventional OSEM (3D) and motion-compensated OSEM (3Dcomp). Seven VOI (liver, lungs, tumors, perfused liver, hepatic reserve, healthy perfused liver and healthy liver) were delineated on the CT or obtained by thresholding SPECT images followed by Boolean operations. Absorbed doses were calculated for each reconstruction using Monte Carlo simulations. Percentages of dose difference (PDD) between 3Dcomp and 3D reconstructions were estimated as well as the relative differences for TN ratio and activities to be injected. The amplitude of movement was determined with local rigid registration of the liver between the 3Dcomp reconstructions of the extreme phases of breathing. RESULTS: The mean amplitude of the liver was 9.5 ± 2.7 mm. Medians of PDD were closed to zero for all VOI except for lungs (6.4%) which means that the motion compensation overestimates the absorbed dose to the lungs compared to the 3D reconstruction. The smallest lesions had higher PDD than the largest ones. Between 3D and 3Dcomp reconstructions, means of differences in lung dose and TN ratio were not statistically significant, but in some cases these differences exceed 1 Gy (4/31) and 8% (2/31). The absolute differences in activity were on average 3.1% ± 5.1% and can reach 22.8%. CONCLUSION: The correction of respiratory motion mainly impacts the lung and tumor doses but only for some patients. The largest dose differences are observed for the smallest lesions.

Rationale for Prostate-Specific-Membrane-Antigen-Targeted Radionuclide Theranostic Applied to Metastatic Clear Cell Renal Carcinoma.

Prostate-specific membrane antigen (PSMA), whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma, is also highly expressed in the neovessels of various solid tumors, including clear cell renal cell carcinoma (ccRCC). In the VISION phase III clinical trial, PSMA-targeted radioligand therapy (PRLT) with lutetium 177 demonstrated a 4-month overall survival OS benefit compared to the best standard of care in heavily pretreated metastatic prostate cancer. Despite the improvement in the management of metastatic clear cell renal cell carcinoma (mccRCC) with antiangiogenic tyrosine kinase inhibitor (TKI) and immunotherapy, there is still a need for new treatments for patients who progress despite these drugs. In this study, we discuss the rationale of PRLT applied to the treavtment of mccRCC.

Performance study of a 360° CZT camera for monitoring 177Lu-PSMA treatment.

BACKGROUND: The aim of this study was to investigate the quantification performance of a 360° CZT camera for 177Lu-based treatment monitoring. METHODS: Three phantoms with known 177Lu activity concentrations were acquired: (1) a uniform cylindrical phantom for calibration, (2) a NEMA IEC body phantom for analysis of different-sized spheres to optimise quantification parameters and (3) a phantom containing two large vials simulating organs at risk for tests. Four sets of reconstruction parameters were tested: (1) Scatter, (2) Scatter and Point Spread Function Recovery (PSFR), (3) PSFR only and (4) Penalised likelihood option and Scatter, varying the number of updates (iterations × subsets) with CT-based attenuation correction only. For each, activity concentration (ARC) and contrast recovery coefficients (CRC) were estimated as well as root mean square. Visualisation and quantification parameters were applied to reconstructed patient image data. RESULTS: Optimised quantification parameters were determined to be: CT-based attenuation correction, scatter correction, 12 iterations, 8 subsets and no filter. ARC, CRC and RMS results were dependant on the methodology used for calculations. Two different reconstruction parameters were recommended for visualisation and for quantification. 3D whole-body SPECT images were acquired and reconstructed for 177Lu-PSMA patients in 2-3 times faster than the time taken for a conventional gamma camera. CONCLUSION: Quantification of whole-body 3D images of patients treated with 177Lu-PSMA is feasible and an optimised set of parameters has been determined. This camera greatly reduces procedure time for whole-body SPECT.

Patient-specific dosimetry adapted to variable number of SPECT/CT time-points per cycle for [Formula: see text]Lu-DOTATATE therapy.

BACKGROUND: The number of SPECT/CT time-points is important for accurate patient dose estimation in peptide receptor radionuclide therapy. However, it may be limited by the patient's health and logistical reasons. Here,  an image-based dosimetric workflow adapted to the number of SPECT/CT acquisitions available throughout the treatment cycles was proposed, taking into account patient-specific pharmacokinetics and usable in clinic for all organs at risk. METHODS: Thirteen patients with neuroendocrine tumors were treated with four injections of 7.4 GBq of [Formula: see text]Lu-DOTATATE. Three SPECT/CT images were acquired during the first cycle (1H, 24H and 96H or 144H post-injection) and a single acquisition (24H) for following cycles. Absorbed doses were estimated for kidneys (LK and RK), liver (L), spleen (S), and three surrogates of bone marrow (L2 to L4, L1 to L5 and T9 to L5) that were compared. 3D dose rate distributions were computed with Monte Carlo simulations. Voxel dose rates were averaged at the organ level. The obtained Time Dose-Rate Curves (TDRC) were fitted with a tri-exponential model and time-integrated. This method modeled patient-specific uptake and clearance phases observed at cycle 1. Obtained fitting parameters were reused for the following cycles, scaled to the measure organ dose rate at 24H. An alternative methodology was proposed when some acquisitions were missing based on population average TDRC (named STP-Inter). Seven other patients with three SPECT/CT acquisitions at cycles 1 and 4 were included to estimate the uncertainty of the proposed methods. RESULTS: Absorbed doses (in Gy) per cycle available were: 3.1 ± 1.1 (LK), 3.4 ± 1.5 (RK), 4.5 ± 2.8 (L), 4.6 ± 1.8 (S), 0.3 ± 0.2 (bone marrow). There was a significant difference between bone marrow surrogates (L2 to L4 and L1 to L5, Wilcoxon's test: p value < 0.05), and while depicting very doses, all three surrogates were significantly different than dose in background (p value < 0.01). At cycle 1, if the acquisition at 24H is missing and approximated, medians of percentages of dose difference (PDD) compared to the initial tri-exponential function were inferior to 3.3% for all organs. For cycles with one acquisition, the median errors were smaller with a late time-point. For STP-Inter, medians of PDD were inferior to 7.7% for all volumes, but it was shown to depend on the homogeneity of TDRC. CONCLUSION: The proposed workflow allows the estimation of organ doses, including bone marrow, from a variable number of time-points acquisitions for patients treated with [Formula: see text]Lu-DOTATATE.

Yttrium-90 quantitative phantom study using digital photon counting PET.

BACKGROUND: PET imaging of 90Y-microsphere distribution following radioembolisation is challenging due to the count-starved statistics from the low branching ratio of e+/e- pair production during 90Y decay. PET systems using silicon photo-multipliers have shown better 90Y image quality compared to conventional photo-multiplier tubes. The main goal of the present study was to evaluate reconstruction parameters for different phantom configurations and varying listmode acquisition lengths to improve quantitative accuracy in 90Y dosimetry, using digital photon counting PET/CT. METHODS: Quantitative PET and dosimetry accuracy were evaluated using two uniform cylindrical phantoms specific for PET calibration validation. A third body phantom with a 9:1 hot sphere-to-background ratio was scanned at different activity concentrations of 90Y. Reconstructions were performed using OSEM algorithm with varying parameters. Time-of-flight and point-spread function modellings were included in all reconstructions. Absorbed dose calculations were carried out using voxel S-values convolution and were compared to reference Monte Carlo simulations. Dose-volume histograms and root-mean-square deviations were used to evaluate reconstruction parameter sets. Using listmode data, phantom and patient datasets were rebinned into various lengths of time to assess the influence of count statistics on the calculation of absorbed dose. Comparisons between the local energy deposition method and the absorbed dose calculations were performed. RESULTS: Using a 2-mm full width at half maximum post-reconstruction Gaussian filter, the dosimetric accuracy was found to be similar to that found with no filter applied but also reduced noise. Larger filter sizes should not be used. An acquisition length of more than 10 min/bed reduces image noise but has no significant impact in the quantification of phantom or patient data for the digital photon counting PET. 3 iterations with 10 subsets were found suitable for large spheres whereas 1 iteration with 30 subsets could improve dosimetry for smaller spheres. CONCLUSION: The best choice of the combination of iterations and subsets depends on the size of the spheres. However, one should be careful on this choice, depending on the imaging conditions and setup. This study can be useful in this choice for future studies for more accurate 90Y post-dosimetry using a digital photon counting PET/CT.

Monte Carlo simulation of digital photon counting PET.

A GATE Monte Carlo model of the Philips Vereos digital photon counting PET imaging system using silicon photo-multiplier detectors was proposed. It was evaluated against experimental data in accordance with NEMA guidelines. Comparisons were performed using listmode data in order to remain independent of image reconstruction algorithms. An original line of response-based method is proposed to estimate intrinsic spatial resolution without reconstruction. Four sets of experiments were performed: (1) count rates and scatter fraction, (2) energy and timing resolutions, (3) sensitivity, and (4) intrinsic spatial resolution. Experimental and simulated data were found to be in good agreement, with overall differences lower than 10% for activity concentrations used in most standard clinical applications. Illustrative image reconstructions were provided. In conclusion, the proposed Monte Carlo model was validated and can be used for numerous studies such as optimizing acquisition parameters or reconstruction algorithms.

Image-based SPECT calibration based on the evaluation of the Fraction of Activity in the Field of View.

BACKGROUND: SPECT quantification is important for dosimetry in targeted radionuclide therapy (TRT) and the calibration of SPECT images is a crucial stage for image quantification. The current standardized calibration protocol (MIRD 23) uses phantom acquisitions to derive a global calibration factor in specific conditions. It thus requires specific acquisitions for every clinical protocols. We proposed an alternative and complementary image-based calibration method that allows to determine a calibration factor adapted to each patient, radionuclide, and acquisition protocol and that may also be used as an additional independent calibration. RESULTS: The proposed method relies on a SPECT/CT acquisition of a given region of interest and an initial whole-body (WB) planar image. First, the conjugate view of WB planar images is computed after scatter and attenuation correction. 3D SPECT images are reconstructed with scatter, attenuation, and collimator-detector response (CDR) corrections and corrected from apparent dead-time. The field of view (FOV) of the SPECT image is then projected on the corrected WB planar image. The fraction of activity located in the area corresponding to the SPECT FOV is then calculated based on the counts on the corrected WB planar image. The Fraction of Activity in Field Of View (FAF) is then proposed to compute the calibration factor as the total number of counts in the SPECT image divided by this activity. Quantification accuracy was compared with the standard calibration method both with phantom experiments and on patient data. Both standard and image-based calibrations give good accuracy on large region of interest on phantom experiments (less than 7% of relative difference compared to ground truth). Apparent dead-time correction allows to reduce the uncertainty associated with standard calibration from 2.5 to 1%. The differences found between both methods were lower than the uncertainty range of the standard calibration (<3%). In patient data, although no ground truth was available, both methods give similar calibration factor (average difference 3.64%). CONCLUSIONS: A calibration factor may be computed directly from the acquired SPECT image providing that a WB planar image is also available and if both acquisitions are performed before biological elimination. This method does not require to perform phantom acquisition for every different acquisition conditions and may serve to double check the calibration with an independent factor.

Voxel-based multimodel fitting method for modeling time activity curves in SPECT images.

PURPOSE: Estimating the biodistribution and the pharmacokinetics from time-sequence SPECT images on a per-voxel basis is useful for studying activity nonuniformity or computing absorbed dose distributions by convolution of voxel kernels or Monte-Carlo radiation transport. Current approaches are either region-based, thus assuming uniform activity within the region, or voxel-based but using the same fitting model for all voxels. METHODS: We propose a voxel-based multimodel fitting method (VoMM) that estimates a fitting function for each voxel by automatically selecting the most appropriate model among a predetermined set with Akaike criteria. This approach can be used to compute the time integrated activity (TIA) for all voxels in the image. To control fitting optimization that may fail due to excessive image noise, an approximated version based on trapezoid integration, named restricted method, is also studied. From this comparison, the number of failed fittings within images was estimated and analyzed. Numerical experiments were used to quantify uncertainties and feasibility was demonstrated with real patient data. RESULTS: Regarding numerical experiments, root mean square errors of TIA obtained with VoMM were similar to those obtained with bi-exponential fitting functions, and were lower (< 5% vs.  > 10%) than with single model approaches that consider the same fitting function for all voxels. Failure rates were lower with VoMM and restricted approaches than with single-model methods. On real clinical data, VoMM was able to fit 90% of the voxels and led to less failed fits than single-model approaches. On regions of interest (ROI) analysis, the difference between ROI-based and voxel-based TIA estimations was low, less than 4%. However, the computation of the mean residence time exhibited larger differences, up to 25%. CONCLUSIONS: The proposed voxel-based multimodel fitting method, VoMM, is feasible on patient data. VoMM leads organ-based TIA estimations similar to conventional ROI-based method. However, for pharmacokinetics analysis, studies of spatial heterogeneity or voxel-based absorbed dose assessment, VoMM could be used preferentially as it prevents model overfitting.

3D absorbed dose distribution estimated by Monte Carlo simulation in radionuclide therapy with a monoclonal antibody targeting synovial sarcoma.

BACKROUND: Radiolabeled OTSA101, a monoclonal antibody targeting synovial sarcoma (SS) developed by OncoTherapy Science, was used to treat relapsing SS metastases following a theranostic procedure: in case of significant 111In-OTSA101 tumor uptake and favorable biodistribution, patient was randomly treated with 370/1110 MBq 90Y-OTSA101. Monte Carlo-based 3D dosimetry integrating time-activity curves in VOI was performed on 111In-OTSA101 repeated SPECT/CT. Estimated absorbed doses (AD) in normal tissues were compared to biological side effects and to the admitted maximal tolerated absorbed dose (MTD) in normal organs. Results in the tumors were also compared to disease evolution. RESULTS: Biodistribution and tracer quantification were analyzed on repeated SPECT/CT acquisitions performed after injection of 111In-OTSA101 in 19/20 included patients. SPECT images were warped to a common coordinates system with deformable registration. Volumes of interest (VOI) for various lesions and normal tissues were drawn on the first CT acquisition and reported to all the SPECT images. Tracer quantification and residence time of 111In-OTSA101 in VOI were used to evaluate the estimated absorbed doses per MBq of 90Y-OTSA101 by means of Monte Carlo simulations (GATE). A visual scale analysis was applied to assess tumor uptake (grades 0 to 4) and results were compared to the automated quantification. Results were then compared to biological side effects reported in the selected patients treated with 90Y-OTSA101 but also to disease response to treatment. After screening, 8/20 patients were treated with 370 or 1110 MBq 90Y-OTSA101. All demonstrated medullary toxicity, only one presented with transient grade 3 liver toxicity due to disease progression, and two patients presented with transient grade 1 renal toxicity. Median absorbed doses were the highest in the liver (median, 0.64 cGy/MBq; [0.27 -1.07]) being far lower than the 20 Gy liver MTD, and the lowest in bone marrow (median, 0.09 cGy/MBq; [0.02 -0.18]) being closer to the 2 Gy bone marrow MTD. Most of the patients demonstrated progressive disease on RECIST criteria during patient follow-up. 111In-OTSA101 tumors tracer uptake visually appeared highly heterogeneous in inter- and intra-patient analyses, independently of tumor sizes, with variable kinetics. The majority of visual grades corresponded to the automated computed ones. Estimated absorbed doses in the 95 supra-centimetric selected lesions ranged from 0.01 to 0.71 cGy per injected MBq (median, 0.22 cGy/MBq). The maximal tumor AD obtained was 11.5 Gy. CONCLUSIONS: 3D dosimetry results can explain the observed toxicity and tumors response. Despite an intense visual 111In-OTSA101 liver uptake, liver toxicity was not the dose limiting factor conversely to bone marrow toxicity. Even though tumors 111In-OTSA101 avidity was visually obvious for treated patients, the low estimated tumors AD obtained by 3D dosimetry explain the lack of tumor response.

Nonrigid registration method to assess reproducibility of breath-holding with ABC in lung cancer.

PURPOSE: To study the interfraction reproducibility of breath-holding using active breath control (ABC), and to develop computerized tools to evaluate three-dimensional (3D) intrathoracic motion in each patient. METHODS AND MATERIALS: Since June 2002, 11 patients with non-small-cell lung cancer enrolled in a Phase II trial have undergone four CT scans: one during free-breathing (reference) and three using ABC. Patients left the room between breath-hold scans. The patient's breath was held at the same predefined phase of the breathing cycle (about 70% of the vital capacity) using the ABC device, then patients received 3D-conformal radiotherapy. Automated computerized tools for breath-hold CT scans were developed to analyze lung and tumor interfraction residual motions with 3D nonrigid registration. RESULTS: All patients but one were safely treated with ABC for 7 weeks. For 6 patients, the lung volume differences were <5%. The mean 3D displacement inside the lungs was between 2.3 mm (SD 1.4) and 4 mm (SD 3.3), and the gross tumor volume residual motion was 0.9 mm (SD 0.4) to 5.9 mm (SD 0.7). The residual motion was slightly greater in the inferior part of the lung than the superior. For 2 patients, we detected volume changes >300 cm(3) and displacements >10 mm, probably owing to atelectasia and emphysema. One patient was excluded, and two others had incomplete data sets. CONCLUSION: Breath-holding with ABC was effective in 6 patients, and discrepancies were clinically accountable in 2. The proposed 3D nonrigid registration method allows for personalized evaluation of breath-holding reproducibility with ABC. It will be used to adapt the patient-specific internal margins.