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A novel planar image-based method for bone marrow dosimetry in (177)Lu-DOTATATE treatment correlates with haematological toxicity.

ABSTRACT: BACKGROUND:(?177)Lu-DOTATATE is a valuable treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. Though well tolerated in general, bone marrow toxicity can, besides renal exposure, become dose limiting and affect the ability to sustain future therapies. The aim of this study was to develop a novel planar image-based method for bone marrow dosimetry and evaluate its correlation with haematological toxicity during (177)Lu-DOTATATE treatment. In this study, 46 patients with advanced neuroendocrine tumours were treated with 7.2 GBq (3.5-8.3 GBq) of (177)Lu-DOTATATE on two to five occasions. Planar gamma camera images were acquired at 2, 24, 48 and 168 h post-injection. Whole-body regions of interest were created in the images, and a threshold-based segmentation algorithm was applied to separate the uptake of (177)Lu-DOTATATE into high and low uptake compartments. The conjugate view method was used to quantify the activity, the accumulated activity was calculated and the absorbed dose to the bone marrow was estimated according to the MIRD scheme. Patients were monitored for haematological toxicity based on haemoglobin (Hb), white blood cell (WBC) and platelet (PLT) counts every other week during the treatment period. RESULTS:The mean absorbed dose to the bone marrow was estimated to 0.20 Gy (0.11-0.37 Gy) per 7.4 GBq of (177)Lu-DOTATATE, and the mean dose per fraction correlated with a decrease in Hb (p?=?0.01), WBC (p?

SUBMITTER: Svensson J

PROVIDER: S-EPMC5031567 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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A novel planar image-based method for bone marrow dosimetry in (177)Lu-DOTATATE treatment correlates with haematological toxicity.

Svensson Johanna J Rydén Tobias T Hagmarker Linn L Hemmingsson Jens J Wängberg Bo B Bernhardt Peter P

EJNMMI physics 20160922 1

<h4>Background</h4>(177)Lu-DOTATATE is a valuable treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. Though well tolerated in general, bone marrow toxicity can, besides renal exposure, become dose limiting and affect the ability to sustain future therapies. The aim of this study was to develop a novel planar image-based method for bone marrow dosimetry and evaluate its correlation with haematological toxicity during (177)Lu-DOTATATE treatme ...[more]

PMID: 27654452

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Project description:This study aimed to compare different image-based methods for bone marrow dosimetry and study the dose-response relationship during treatment with 177Lu-DOTATATE in patients with and without skeletal metastases. Methods: This study included 46 patients with advanced neuroendocrine tumors treated with at least 2 fractions of 177Lu-DOTATATE at Sahlgrenska University Hospital. High- and low-uptake compartments were automatically outlined in planar images collected at 2, 24, 48, and 168 h after injection. The bone marrow absorbed doses were calculated from the cross doses of the high- and low-uptake compartments and the self-dose, using the time-activity concentration curve for the low-uptake compartment. This time-activity concentration curve was adjusted using a fixed constant of 1.8 for the planar dosimetry method and using the activity concentrations in vertebral bodies in SPECT images at 24 h after injection of 177Lu-DOTATATE in 4 hybrid methods: L4-SPECT used the activity concentration in the L4 vertebra, whereas V-SPECT, L-SPECT, and T-SPECT used the median activity concentration in all visible vertebrae, lumbar vertebrae, and thoracic vertebrae, respectively. Results: Using the planar method, L4-SPECT, V-SPECT, L-SPECT, and T-SPECT, the estimated median bone marrow absorbed doses were 0.19, 0.36, 0.40, 0.39, and 0.46 Gy/7.4 GBq, respectively, with respective ranges of 0.12-0.33, 0.15-1.44, 0.19-1.71, 0.21-1.60, and 0.18-2.12 Gy/7.4 GBq. For all methods, the bone marrow absorbed dose significantly correlated with decreased platelet counts. This correlation increased after treatment fraction 2: the Spearman correlation (r s) were -0.49 for the planar method, -0.61 for L4-SPECT, -0.63 for V-SPECT, -0.63 for L-SPECT, and -0.57 for T-SPECT. A separate analysis revealed an increased correlation for patients without skeletal metastases using the planar method (r s = -0.67). In contrast, hybrid methods had poor correlations for patients without metastases and stronger correlations for patients with skeletal metastases (r s = -0.61 to -0.74). The mean bone marrow absorbed doses were 3%-69% higher for patients with skeletal metastases than for patients without. Conclusion: The estimated bone marrow absorbed doses by image-based techniques and the correlation with platelets are influenced by the choice of measured vertebrae and the presence of skeletal metastases.

Project description:PurposeFractionated peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE is increasingly applied as an effective treatment for patients with disseminated neuroendocrine tumors. In parallel to dose planning before external beam radiation therapy, dosimetry is also needed to optimize PRRT to the individual patient. Accordingly, absorbed doses to organs at risk need to be calculated during PRRT, based on serial measurements of radioactivity distribution utilizing SPECT/CT. The dosimetry should be based on as few measurements as possible, while still retaining reliable results. The main aim of the present work was to calculate the fractional contribution of the extrapolations of the curve fits for the absorbed dose calculations to the kidneys. The secondary aim was to study agreement between absorbed dose (AD) and the effective half-life (teff) for the kidneys, estimated by means of measurements at one or two time points, in comparison to our current method employing three time points.MethodsIn 777 patients with disseminated neuroendocrine tumors undergoing PRRT, SPECT/CT over the abdomen was acquired at 1, 4, and 7 days after 177Lu-DOTATATE infusion. The absorbed dose to the kidneys was calculated from SPECT/CT radioactivity distribution data, and the teff and fractional contributions of the extrapolations were estimated, utilizing data from one, two, and three time points, respectively.ResultsThe fractional contributions from extrapolations before day 1 measurement and after day 7 measurement were approximately 26% and 11%, respectively. The mean differences in absorbed dose, based on one, two, and three time points were small, but with high method dependence for individual patients. The differences in estimated teff were small when it was based on measurements at days 1 and 7, but high for days 1 and 4 time points.ConclusionWhen assessing simplifications of methods for calculation of the absorbed dose to the kidneys, it was of the uttermost importance to incorporate the fractional contribution for the extrapolations included in the reference method. Measurements at an early and a late time point were found most important. An intermediate measurement contributes with an idea of the goodness of the fit.

Project description:177Lu-DOTATATE (Lutathera®) enables targeted radionuclide therapy of neuroendocrine tumors expressing somatostatin receptor type 2. Though patient-specific dosimetry estimates may be clinically important for predicting absorbed dose-effect relationships, there are multiple relevant dosimetry paradigms which are distinct in terms of clinical effort, numerical output and added-value. This work compares three different approaches for177Lu-DOTATATE dosimetry, including 1) an organ-level approach based on reference phantom MIRD S-values scaled to patient-specific organ masses (MIRDcalc), 2) an organ-level approach based on Monte Carlo simulation in a patient-specific mesh phantoms (PARaDIM), and 3) a 3D approach based on Monte Carlo simulation in patient-specific voxel phantoms.Method. Serial quantitative SPECT/CT images for two patients receiving177Lu-DOTATATE therapy were obtained from archive in theDeep Bluedatabase. For each patient, the serial CT images were co-registered to the first time point CT using a deformable registration technique aided by virtual landmarks placed in the kidney pelves and the lesion foci. The co-registered SPECT images were integrated voxel-wise to generate time-integrated activity maps. Lesions, kidneys, liver, spleen, lungs, compact bone, spongiosa, and rest of body were segmented at the first imaging time point and overlaid on co-registered integrated activity maps. The resultant segmentation was used for three purposes: 1) to generate patient-specific phantoms, 2) to determine organ-level time-integrated activities, and 3) to generate dose volume histograms from 3D voxel-based calculations.Results. Mean absorbed doses were computed for lesions and 48 tissues with MIRDcalc software. Mean organ absorbed doses and dose volume histograms were obtained for lesions and 6 tissues with the voxel Monte Carlo approach. Lesion- and organ-level absorbed dose estimates agreed within ±26% for the lesions and ±13% for the critical organs, among the different methods tested. Overall good agreement was observed with the dosimetry estimates from the NETTER-1 trial.Conclusions. For personalized177Lu-DOTATATE dosimetry, a combined approach was determined to be valuable, which utilized two dose calculation methods supported by a single image processing workflow. In the absence of quantitative imaging limitations, the voxel Monte Carlo method likely provides valuable information to guide treatment by considering absorbed dose non-uniformity in lesions and organs at risk. The patient-scaled reference phantom method also provides valuable information, including absorbed dose estimates for non-segmented organs, and more accurate dose estimates for complex radiosensitive organs including the active marrow.

Project description:BACKGROUND:Radionuclide therapy can be individualized by performing dosimetry. To determine absorbed organ doses in (177)Lu-DOTATATE therapy, three methods based on activity concentrations are currently in use: the small volume of interest (sVOI) method, and two methods based on large VOIs either on anatomical CT (aVOI) or on thresholds on functional images (tVOI). The main aim of the present work was to validate the sVOI in comparison to the other two methods regarding agreement and time efficiency. Secondary aims were to investigate inter-observer variability for the sVOI and the change of functional organ volumes following therapy. METHODS:Thirty patients diagnosed with neuroendocrine tumours undergoing therapy with (177)Lu-DOTATATE were included. Each patient underwent three SPECT/CT scans at 1, 4 and 7 days after the treatment. Three independent observers calculated absorbed doses to the right and left kidney and the spleen using sVOI and one observer used aVOI. For tVOI, the absorbed doses were calculated based on automatically drawn isocontours around the organs at different thresholds (42, 50, 60 and 70 %). The inter-observer difference between the calculated absorbed doses for sVOI was calculated, and the differences between the three methods were computed. Ratios of organ volumes acquired at days 1, 4 and 7 versus the volume at day 1 were calculated for the tVOI method. RESULTS:The differences in results of the absorbed dose calculations using all the sVOI and tVOI were small (<5 %). Absorbed dose calculations using aVOI differed slightly more from these results but were still below 10 %. The differences between the three dose calculation methods varied between <5 and 10 %. The organ volumes derived from the tVOI were independent of time for the spleen while they decreased with time for the kidneys. The fastest analysis was performed with the sVOI method. CONCLUSIONS:All three dose calculation methods rendered comparable results with small inter-observer differences for sVOI. Unlike the spleen, the functional volume of the kidneys decreased over time during therapy, which suggests that the absorbed dose calculation for the kidneys on activity concentrations should be performed for each time point. The sVOI is the preferred method for calculating absorbed doses in solid organs.

Project description:BackgroundIndividualized dosimetry is recommended for [177Lu]Lu-PSMA radioligand therapy (RLT) which is resource-intensive and protocols are often not optimized. Therefore, a simulation study was performed focusing on the determination of efficient optimal sampling schedules (OSS) for renal and tumour dosimetry by investigating different numbers of time points (TPs).MethodsSampling schedules with 1-4 TPs were investigated. Time-activity curves of the kidneys and two tumour lesions were generated based on a physiologically based pharmacokinetic (PBPK) model and biokinetic data of 13 patients who have undergone [177Lu]Lu-PSMA I&T therapy. Systematic and stochastic noise of different ratios was considered when modelling time-activity data sets. Time-integrated activity coefficients (TIACs) were estimated by simulating the hybrid planar/SPECT method for schedules comprising at least two TPs. TIACs based on one single SPECT/CT measurement were estimated using an approximation for reducing the number of fitted parameters. For each sampling schedule, the root-mean-squared error (RMSE) of the deviations of the simulated TIACs from the ground truths for 1000 replications was used as a measure for accuracy and precision.ResultsAll determined OSS included a late measurement at 192 h p.i., which was necessary for accurate and precise tumour TIACs. OSS with three TPs were identified to be 3-4, 96-100 and 192 h with an additional SPECT/CT measurement at the penultimate TP. Kidney and tumour RMSE of 6.4 to 7.7% and 6.3 to 7.8% were obtained, respectively. Shortening the total time for dosimetry to e.g. 96 h resulted in kidney and tumour RMSE of 6.8 to 8.3% and 9.1 to 11%, respectively. OSS with four TPs showed similar results as with three TPs. Planar images at 4 and 68 h and a SPECT/CT shortly after the 68 h measurement led to kidney and tumour RMSE of 8.4 to 12% and 12 to 16%, respectively. One single SPECT/CT measurement at 52 h yielded good approximations for the kidney TIACs (RMSE of 7.0%), but led to biased tumour TIACs.ConclusionOSS allow improvements in accuracy and precision of renal and tumour dosimetry for [177Lu]Lu-PSMA therapy with potentially less effort. A late TP is important regarding accurate tumour TIACs.

Project description:PurposeRadionuclide therapy with 177Lu-DOTATATE is well established for patients with advanced somatostatin receptor-positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk. Therefore, it is important to assess more personalized strategies. The aim of this phase II trial was to evaluate individualized 177Lu-DOTATATE for which the number of cycles varied based on renal dosimetry.MethodsPatients were eligible if they had a progressive, somatostatin receptor-positive neuroendocrine tumor with a Ki 67 labeling index < 20%. They received cycles of 7.4 GBq of 177Lu-DOTATATE at 10 ± 2-week intervals until a predefined radiation dose to the kidneys was reached. The primary endpoint was objective tumor response (RECIST v 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity (CTCAE v. 4.0).ResultsNinety-six patients who had received a median of 5 cycles (range 1-9) were evaluable for efficacy. The objective tumor response was 16% partial response, 66% stable disease, and 19% progressive disease. The median PFS and OS were 29 months and 47 months, respectively, and were significantly associated with kidney dose, performance status, and Ki 67 levels but not with tumor origin. The overall toxicity was mild, and the most common events were grade 1-2 anemia, thrombocytopenia, fatigue, nausea, and diarrhea. Grade 3-4 toxicity occurred in < 10% of patients and was mostly hematological, with no grade 3-4 renal toxicity.ConclusionIndividualized treatment with 177Lu-DOTATATE based on renal dosimetry is clearly feasible with low toxicity and promising efficacy, showing the potential to further improve outcome beyond the standard approach, and should be further assessed in randomized trials.Trial registrationEudraCT 2011-000,240-16. NCT01456078. https://clinicaltrials.gov/ct2/show/NCT01456078.

Project description:BackgroundRadiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice.ResultsrhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3-0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6-11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively.ConclusionOur preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).

Dataset Information

A novel planar image-based method for bone marrow dosimetry in (177)Lu-DOTATATE treatment correlates with haematological toxicity.

Publications

A novel planar image-based method for bone marrow dosimetry in (177)Lu-DOTATATE treatment correlates with haematological toxicity.

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