Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial

Prete, Michela Del; Buteau, François-Alexandre; Arsenault, Frédéric; Saighi, Nassim; Bouchard, Louis-Olivier; Beaulieu, Alexis; Beauregard, Jean-Mathieu

doi:10.1007/s00259-018-4209-7

Cited by 135 publications

(107 citation statements)

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“…These two approaches resulted in increased cumulative IA and tumor absorbed dose in the majority of patients [ 4 , 6 ]. Further, when administering personalized IA, our preliminary results suggest a similar short-term side effect and toxicity profile as those observed when using the empiric PRRT regime [ 10 ]. Although our outcome data is not yet mature enough to document significantly improved clinical outcomes, nevertheless, we believe that personalized radionuclide therapy is more faithful to the principles of radiation oncology, where the absorbed doses are prescribed and monitored.…”

Section: Discussionmentioning

confidence: 63%

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

et al. 2018

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BackgroundRoutine 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.MethodsSeventy-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.ResultsThe 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 eG...

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Section: Discussionmentioning

confidence: 63%

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

et al. 2018

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“…Although 177 Lu-DOTATATE, 90 Y-DOTATOC -and, increasingly, 177 Lu-PSMA (Prostate Specific Membrane Antigen) -are widely used throughout Europe, therapy invariably consists of 2 or 4 intravenous administrations of 7.4 GBq, separated by nine to twelve weeks, mostly regardless of the patient's size, weight, the extent of positive 111 In-octreotide or 68 Ga-DOTATATE uptake (measured by SPECT or PET imaging, respectively), or inherent radiosensitivity of the tumor or patient (8,9). Importantly, most MRT dosimetry and radiobiology has been based on EBRT data, due to a paucity in radiobiological data of radionuclide therapy (10). This substitution of EBRT for MRT dosimetry cannot adequately account for the distinct and complex cellular localization of ionising radiation with MRT, and the distinctly different dynamic biological response across the timeframe of exposure during MRT.…”

Section: Introductionmentioning

confidence: 99%

Imaging DNA Damage Repair In Vivo After ¹⁷⁷Lu-DOTATATE Therapy

et al. 2019

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Purpose. Molecular Radiotherapy (MRT) using 177 Lu-DOTATATE is a most effective therapy for the treatment of somatostatin receptor expressing neuroendocrine tumors (NETs). Despite its frequent and successful use in the clinic, little or no radiobiological considerations are taken into account at the time of treatment planning or delivery, and upon positive uptake of octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiological and DNA damage effects in the tumor. Here, we visualize and quantify the extent of DNA damage response following 177 Lu-DOTATATE therapy using SPECT imaging with 111 In-anti-γH2AX-TAT. This work is a proof-of-principle study of this in vivo non-invasive biodosimeter with beta-emitting therapeutic radiopharmaceuticals. Methods. Six cell lines were exposed to external beam radiotherapy (EBRT) or 177 Lu-DOTATATE, after which the number of γH2AX foci and clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor positive tumor xenografts were treated with 177 Lu-DOTATATE or sham-treated, and co-injected with 111 In-anti-γH2AX-TAT, 111 In-IgG-TAT control, or vehicle. Results. Clonogenic survival following EBRT was cell line specific, indicating varying levels of intrinsic radiosensitivity. In vitro, cell lines treated with 177 Lu-DOTATATE, clonogenic survival decreased and γH2AX foci increased in cells expressing high levels of somatostatin receptor subtype 2 (SST2). Ex vivo measurements revealed a partial correlation between 177 Lu-DOTATATE uptake and γH2AX foci induction between different regions of CA20948 xenograft tumors, suggesting different parts of the tumor may react differentially to 177 Lu-DOTATATE irradiation. Conclusion. 111 In-anti-γH2AX-TAT allows monitoring of DNA damage following 177 Lu-DOTATATE therapy, and reveals heterogeneous damage responses.

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“…four cycles of 7.4 GBq 177 Lu-DOTA-octreotate), despite the well-known high inter-patient variability of absorbed doses to healthy tissues per injected activity [3][4][5]. There is growing evidence that personalizing PRRT based on image-based dosimetry calculations could enhance its efficacy without augmenting toxicity, by increasing injected activity and tumour irradiation in a majority of patients, while limiting radiation exposure of their healthy tissues [3][4][5]. Dosimetry-based personalization could also benefit the rapidly developing prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) with 177 Lu [6].…”

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Comprehensive SPECT/CT system characterization and calibration for 177Lu quantitative SPECT (QSPECT) with dead-time correction

Frezza

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et al. 2020

EJNMMI Phys

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Background: Personalization of 177 Lu-based radionuclide therapy requires implementation of dosimetry methods that are both accurate and practical enough for routine clinical use. Quantitative single-photon emission computed tomography/ computed tomography (QSPECT/CT) is the preferred scanning modality to achieve this and necessitates characterizing the response of the camera, and calibrating it, over the full range of therapeutic activities and system capacity. Various methods to determine the camera calibration factor (CF) and the deadtime constant (τ) were investigated, with the aim to design a simple and robust protocol for quantitative 177 Lu imaging. Methods: The SPECT/CT camera was equipped with a medium energy collimator. Multiple phantoms were used to reproduce various attenuation conditions: rod sources in air or water-equivalent media, as well as a Jaszczak phantom with inserts. Planar and tomographic images of a wide range of activities were acquired, with multiple energy windows for scatter correction (double or triple energy window technique) as well as count rate monitoring over a large spectrum of energy. Dead time was modelled using the paralysable model. CF and τ were deduced by curve fitting either separately in two steps (CF determined first using a subset of low-activity acquisitions, then τ determined using the full range of activity) or at once (both CF and τ determined using the full range of activity). Total or segmented activity in the SPECT field of view was computed. Finally, these methods were compared in terms of accuracy to recover the known activity, in particular when planar-derived parameters were applied to the SPECT data. Results: The SPECT camera was shown to operate as expected on a finite count rate range (up to~350 kcps over the entire energy spectrum). CF and τ from planar (sources in air) and SPECT segmented Jaszczak data yielded a very good agreement (CF < 1% and τ < 3%). Determining CF and τ from a single curve fit made deadtime-corrected images less prone to overestimating recovered activity. Using tripleenergy window scatter correction while acquiring one or more additional energy window(s) to enable wide-spectrum count rate monitoring (i.e. ranging 55-250 or 18-680 keV) yielded the most consistent results across the various geometries. The final, planar-derived calibration parameters for our system were a CF of 9.36 ± 0.01 cps/MBq and a τ of 0.550 ± 0.003 μs. Using the latter, the activity in a Jaszczak phantom could be quantified by QSPECT with an accuracy of 0.02 ± 1.10%.

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Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial

Cited by 135 publications

References 24 publications

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

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

Imaging DNA Damage Repair In Vivo After ¹⁷⁷Lu-DOTATATE Therapy

Comprehensive SPECT/CT system characterization and calibration for 177Lu quantitative SPECT (QSPECT) with dead-time correction

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Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial

Cited by 135 publications

References 24 publications

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

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

Imaging DNA Damage Repair In Vivo After 177Lu-DOTATATE Therapy

Comprehensive SPECT/CT system characterization and calibration for 177Lu quantitative SPECT (QSPECT) with dead-time correction

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Imaging DNA Damage Repair In Vivo After ¹⁷⁷Lu-DOTATATE Therapy