Abstract The purpose of the EANM Dosimetry Committee is to provide recommendations and guidance to scientists and clinicians on patient-specific dosimetry. Radiopharmaceuticals labelled with lutetium-177 (177Lu) are increasingly used for therapeutic applications, in particular for the treatment of metastatic neuroendocrine tumours using ligands for somatostatin receptors and prostate adenocarcinoma with small-molecule PSMA-targeting ligands. This paper provides an overview of reported dosimetry data for these therapies and summarises current knowledge about radiation-induced side effects on normal tissues and dose-effect relationships for tumours. Dosimetry methods and data are summarised for kidneys, bone marrow, salivary glands, lacrimal glands, pituitary glands, tumours, and the skin in case of radiopharmaceutical extravasation. Where applicable, taking into account the present status of the field and recent evidence in the literature, guidance is provided. The purpose of these recommendations is to encourage the practice of patient-specific dosimetry in therapy with 177Lu-labelled compounds. The proposed methods should be within the scope of centres offering therapy with 177Lu-labelled ligands for somatostatin receptors or small-molecule PSMA. 

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EANM dosimetry committee recommendations for dosimetry of 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands

Routine dosimetry is essential for personalized 177Lu-octreotate peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs), but practical and robust dosimetry methods are needed for wide clinical adoption. The aim of this study was to assess the accuracy and inter-observer reproducibility of simplified dosimetry protocols based on quantitative single-photon emission computed tomography (QSPECT) with a limited number of scanning time points. We also updated our personalized injected activity (IA) prescription scheme. Seventy-nine NET patients receiving 177Lu-octreotate therapy (with a total of 279 therapy cycles) were included in our study. Three-time-point (3TP; days 0, 1, and 3) QSPECT scanning was performed following each therapy administration. Dosimetry was obtained using small volumes of interest activity concentration sampling for the kidney, the bone marrow and the tumor having the most intense uptake. Accuracy of the simplified dosimetry based on two-time-point (2TP; days 1 and 3, monoexponential fit) or a single-time-point (1TPD3; day 3) scanning was assessed, as well as that of hybrid methods based on 2TP for the first cycle and 1TP (day 1 or 3; 2TP/1TPD1 and 2TP/1TPD3, respectively) or no imaging at all (based on IA only; 2TP/no imaging (NI)) for the subsequent induction cycles. The inter-observer agreement was evaluated for the 3TP, 2TP, and hybrid 2TP/1TPD3 methods using a subset of 60 induction cycles (15 patients). The estimated glomerular filtration rate (eGFR), body size descriptors (weight, body surface area (BSA), lean body weight (LBW)), and products of both were assessed for their ability to predict IA per renal absorbed dose at the first cycle. The 2TP dosimetry estimates correlated highly with those from the 3TP data for all tissues (Spearman r > 0.99, P < 0.0001) with small relative errors between the methods, particularly for the kidney and the tumor, with median relative errors not exceeding 2% and interdecile ranges spanning over less than 6% and 4%, respectively, for the per-cycle and cumulative estimates. For the bone marrow, the errors were slightly greater (median errors < 6%, interdecile ranges < 14%). Overall, the strength of correlations of the absorbed dose estimates from the simplified methods with those from the 3TP scans tended to progressively decrease, and the relative errors to increase, in the following order: 2TP, 2TP/1TPD3, 1TPD3, 2TP/1TPD1, and 2TP/NI. For the tumor, the 2TP/NI scenario was highly inaccurate due to the interference of the therapeutic response. There was an excellent inter-observer agreement between the three observers, in particular for the renal absorbed dose estimated using the 3TP and 2TP methods, with mean errors lesser than 1% and standard deviations of 5% or lower. The eGFR · LBW and eGFR · BSA products best predicted the ratio of IA to the renal dose (GBq/Gy) for the first cycle (Spearman r = 0.41 and 0.39, respectively; P < 0.001). For the first cycle, the personalized IA proportional to eGFR · LBW or eGFR · BSA decreased the range of delivered renal absorbed dose between patients as compared with the fixed IA. For the subsequent cycles, the optimal personalized IA could be determined based on the prior cycle renal GBq/Gy with an error of less than 21% in 90% of patients. A simplified dosimetry protocol based on two-time-point QSPECT scanning on days 1 and 3 post-PRRT provides reproducible and more accurate dose estimates than the techniques relying on a single time point for non-initial or all cycles and results in limited patient inconvenience as compared to protocols involving scanning at later time points. Renal absorbed dose over the 4-cycle induction PRRT course can be standardized by personalizing IA based on the product of eGFR with LBW or BSA for the first cycle and on prior renal dosimetry for the subsequent cycles.

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Accuracy and reproducibility of simplified QSPECT dosimetry for personalized 177 Lu-octreotate PRRT.

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 (rs) 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 (rs = −0.67). In contrast, hybrid methods had poor correlations for patients without metastases and stronger correlations for patients with skeletal metastases (rs = −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.

https://jnm.snmjournals.org/content/jnumed/60/10/1406.full.pdf

Bone Marrow Absorbed Doses and Correlations with Hematologic Response During 177Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases

The aims were to decrease 177Lu-SPECT (single-photon emission computed tomography) acquisition time by reducing the number of projections and to circumvent image degradation by adding deep learning–generated synthesized projections.

Methods: We constructed a deep convolutional U-structured network for generating synthetic intermediate projections (CUSIP). The number of SPECT investigations was 352 for training, 37 for validation, and 15 for testing. The input was every fourth projection of 120 acquired SPECT projections, i.e., 30 projections. The output was 30 synthetic intermediate projections (SIPs) per CUSIP. SPECT images were reconstructed with 120 or 30 projections, or 120 projections where 90 SIPs were generated from the 30 projections (30-120SIP); using 3 CUSIPs. The reconstructions were performed with two ordered subset expectation maximization (OSEM) algorithms: attenuation-corrected (AC)-OSEM, and attenuation, scatter, and collimator response–corrected (ASCC)-OSEM. Image quality of SIPs and SPECT images were quantitatively evaluated with root mean square error, peak signal-to-noise-ratio (PSNR), and structural similarity (SSIM) index metrics. From a Jaszczak SPECT Phantom, the recovery and signal-to-noise ratio (SNR) were determined. In addition, an experienced observer qualitatively assessed the SPECT image quality of the test set. Kidney activity concentrations, as determined from the different SPECT images, were compared.

Results: The generated SIPs had a mean SSIM value of 0.926 (0.061). For AC-OSEM, the reconstruction with 30-120SIP had higher SSIM (0.993 vs. 0.989; p<0.001) and PSNR (49.5 vs. 47.2; p<0.001) values than the reconstruction with 30 projections. ASCC-OSEM had higher SSIM and PSNR values than AC-OSEM (p<0.001). There was a minor loss in recovery for the 30-120SIP set, but SNR was clearly improved compared to the 30-projection set. The observer assessed 27/30 of the images reconstructed with 30 projections as having unacceptable noise levels, whereas corresponding values were 2/60 for the 30-120SIP and 120 projection sets. Image quality did not differ significantly between the 30-120SIP and 120 projection reconstructions. The kidney activity concentration was similar between the different projection sets, excepting a minor reduction of 2.5% for the ASCC-OSEM 30-120SIP.

Conclusion: Adopting synthetic intermediate projections for sparsely acquired projections considerably recovers image quality and could allow reduced SPECT acquisition time in clinical dosimetry protocols.

https://jnm.snmjournals.org/content/jnumed/early/2020/08/27/jnumed.120.245548.full.pdf

Deep-Learning Generation of Synthetic Intermediate Projections Improves 177Lu SPECT Images Reconstructed with Sparsely Acquired Projections.

Abstract Purpose Radionuclide therapy with 177 Lu-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 177 Lu-DOTATATE for which the number of cycles varied based on renal dosimetry. Methods Patients were eligible if they had a progressive, somatostatin receptor–positive neuroendocrine tumor with a Ki 67 labeling index &lt; 20%. They received cycles of 7.4 GBq of 177 Lu-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). Results Ninety-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 &lt; 10% of patients and was mostly hematological, with no grade 3–4 renal toxicity. Conclusion Individualized treatment with 177 Lu-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 registration EudraCT 2011–000,240-16. NCT01456078. https://clinicaltrials.gov/ct2/show/NCT01456078 

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Phase II trial demonstrates the efficacy and safety of individualized, dosimetry-based 177Lu-DOTATATE treatment of NET patients

Background: In 177Lu-DOTATATE treatments, bone marrow (BM) is one of the most important organs at risk. The authors previously developed an image-based two-compartment method for BM dosime...

Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments

Linn Hagmarker

Papers

Bone Marrow Absorbed Doses and Correlations with Hematologic Response During 177Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases

Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments