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Purpose: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [ 177 Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs)., Methods: This study was part of a phase I/II trial of [ 177 Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients., Results: In all evaluated organs, maximum [ 177 Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [ 177 Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [ 177 Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles., Conclusion: [ 177 Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy., Trial Registration: NCT02592707. Registered October 30, 2015., (© 2024. The Author(s).)

Purpose: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [ 177 Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity., Methods: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [ 177 Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [ 177 Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 μg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow., Results: Median cumulative administered activity of [ 177 Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment‑related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3-99.4), and overall response rate was 21.1% (95% CI: 9.6-37.3)., Conclusion: [ 177 Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing., Trial Registration: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015., (© 2023. The Author(s).)

Abstract: 68 Ga-DOTATATE PET/CT is indicated for selecting patients for peptide receptor radionuclide therapy (PRRT). Although highly sensitive, the detectability of smaller lesions, particularly in the liver, is lower. We present the case of a 58-year-old man with metastatic well-differentiated pancreatic neuroendocrine tumor whose MRI revealed progression of hepatic metastases. 68 Ga-DOTATATE PET/CT performed to determine eligibility for PRRT did not demonstrate DOTATATE-avid disease within the liver. 18 F-FDG PET/CT was also negative at the liver and the patient proceeded to 177 Lu-DOTATATE PRRT, where multi-time point posttherapy planar imaging and SPECT/CT showed intense uptake in the known liver metastases., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Theranostics - i.e., the combination of molecular imaging and radiopharmaceutical therapy of cancer targeting a common biological feature - is a rapidly expanding field owing the recent successes of novel radiopharmaceutical therapies, such as 177 Lu-based prostate-specific membrane antigen radioligand therapy of prostate cancer and peptide receptor radionuclide therapy of neuroendocrine tumours. Despite the ongoing technical developments in imaging-based dosimetry, the existence of tumour absorbed dose-efficacy and organ absorbed dose-toxicity relationships, as well as the high interpatient variability in absorbed doses per unit activity, radiopharmaceutical therapies are still mostly administered in a fixed-activity, one-size-fits-all fashion. This is at odds with the principles of radiation oncology, where the absorbed doses to tissues are prescribed and their delivery is carefully planned and controlled for each individual patient to maximise the clinical benefits. There is a growing body of clinical evidence that dosimetry-based radiopharmaceutical therapy allows to safely optimise tumour irradiation, which translates into improved clinical outcomes. In this narrative review, we will present the reported prospective clinical experience to date on the use of imaging-based dosimetry to personalise radiopharmaceutical therapies., (© 2022. The Author(s).)

Because of challenges in performing routine personalized dosimetry in radiopharmaceutical therapies, interest in single-time-point (STP) dosimetry, particularly using only a single SPECT scan, is on the rise. Meanwhile, there are questions about the reliability of STP dosimetry, with limited independent validations. In the present work, we analyzed 2 STP dosimetry methods and evaluated dose errors for several radiopharmaceuticals based on effective half-life distributions. Methods: We first challenged the common assumption that radiopharmaceutical effective half-lives across the population are gaussian-distributed (i.e., follow a normal distribution). Then, dose accuracy was estimated using 2 STP dosimetry methods for a wide range of potential post injection (p.i.) scan time points for different radiopharmaceuticals applied to neuroendocrine tumors and prostate cancer. The accuracy and limitations of each of the STP methods were discussed. Results: A lognormal distribution was more appropriate for capturing effective half-life distributions. The STP framework was promising for dosimetry of 177 Lu-DOTATATE and for kidney dosimetry of different radiopharmaceuticals (errors < 30%). Meanwhile, for some radiopharmaceuticals, STP accuracy was compromised (e.g., in bone marrow and tumors for 177 -labeled prostate-specific membrane antigen [PSMA])). The optimal SPECT scanning time for 177 Lu-DOTATATE was approximately 72 h p.i., whereas 48 h p.i. was better for 177 Lu-PSMA. Conclusion: Simplified STP dosimetry methods may compromise the accuracy of dose estimates, with some exceptions, such as for 177 Lu-DOTATATE and for kidney dosimetry in different radiopharmaceuticals. Simplified personalized dosimetry in the clinic continues to be challenging. On the basis of our results, we make suggestions and recommendations for improved personalized dosimetry using simplified imaging schemes., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The incidence of neuroendocrine tumours (NETs) is increasing, but curative therapeutic options are limited because diagnosis is often delayed until the tumour has metastasized. Peptide receptor radionuclide therapy (PRRT) is among the most effective therapeutic options for metastatic NETs because of targeted delivery of radioactivity to the tumour via the somatostatin receptor (SSTR) and relatively low systemic toxicity. However, current PRRT regimes result in palliation rather than cure, and higher doses of PRRT that might achieve remission would also be too toxic to the patients. Therefore, there is a need to improve PRRT of NETs by combining it with other agents to achieve maximum benefits from the internal radiation therapy, while sparing non-target organs from radiation toxicity. Here we review various current and potential combination strategies to improve 177 Lu-octreotate-based PRRT of NET, some of which could also apply to other radionuclide therapies. These strategies include co-administered drugs that improve delivery of the radiopharmaceutical via increased tumour perfusion or through increased SSTR density at tumour surface. Other combinations are aimed at enhancing the biological effects of the radiation-induced DNA damage in tumour cells or generating additional DNA damage burden to effectively increase the cytotoxicity of PRRT. We also propose an algorithm for stratifying NET patients to receive or not combination therapies with PRRT. Considering that PRRT and many of these combination agents are already used for treating patients with NET and other cancers, the proposed strategies to improve the efficacy of PRRT could be rapidly translated into the clinic.

Peptide receptor radionuclide therapy (PRRT) with 177 Lu- radiolabeled octreotate is an effective treatment method for inoperable neuroendocrine tumours (NETs). There is growing evidence that estimates of the organ-at-risks (OARs) doses are necessary for the optimization of personalized PRRT (P-PRRT). Dosimetry, however, requires a complicated and time-consuming procedure, which hinders its implementation in the clinic. The aim of this study is to develop a practical and automatic technique to simplify personalized dosimetry of kidney, the major OAR in 177 Lu P-PRRT. The data from 30 NETs patients undergoing 44 personalized 177 Lu-DOTA-TATE therapy cycles were analyzed. To determine the biokinetics of the radiopharmaceutical in the kidneys, for each patient three SPECT/CT scans were acquired, at about 4 h, 24 h and 70 h after injection. The kidneys doses were evaluated using three different approaches: (1) a traditional approach based on whole kidney (WK) segmentation; (2) a small volume (SV) manual approach (M-SV) with observer-defined SV location; and (3) a software based SV-approach that automatically defines SV location (A-SV). Four different methods of automatic SV location selections were investigated. The SV kidney doses estimated using M-SV and A-SV approaches was evaluated and the accuracy of these two approaches were compared to the WK dosimetry. The kidney bio-kinetics, in terms of effective half-lives, obtained from both of the A-SV and M-SV approaches agreed to within 10% with those obtained from the WK segmentation. The average ratios of SV doses to WK doses were mostly about 1.8  ±  0.2 for both A-SV and M-SV approaches. The linear correlation coefficients between SV doses (both A-SV and M-SV) and WK doses were up to 0.9 with p   <  0.001. The differences between A-SV and M-SV were minor. By comparing different methods of SV location selections, independently selecting SV in images from each of the acquisitions was proved the most appropriate and accurate approach. An automatic, observer-independent method for selecting the location of the small volume in kidneys was developed. The accuracy of this dose estimation approach has been demonstrated by comparing it with the manual SV dosimetry, as well as the WK dosimetry. The proposed automatic approach can potentially be considered as a practical and simple method for dose estimation in the future clinical studies.

177 Lu-DOTATATE therapy has been shown to produce encouraging results in treatment of neuroendocrine tumours (NETs). Unfortunately, since dosimetry for radionuclide therapy is considered to be challenging, typically similar amount of radiopharmaceutical is administered to every patient. There is growing evidence that the efficacy of this therapy can be significantly improved by employing personalized protocols, based on the organ-at-risk dosimetry. The aim of this study is to propose a practical and accurate dosimetry protocol based on the simplified acquisition schedules. Data from fifty-three therapy cycles in thirty-nine NET patients were analyzed. Three SPECT/CT scans, acquired at 4 h (D0), 23 h (D1) and 70 h (D3) after injection, were performed. The kidney volume was determined using CT and the activity was determined from quantitative SPECT using an iterative thresholding method. For each dataset, four methods were used to model the time-activity-curves (TAC): M1-two trapezoid segments (0 to D0 and D0 to D1), followed by monoexponential fit to D1  +  D3 data; M2-monoexponential fit to D0  +  D1  +  D3 data; M3 and M4-monoexponential fit to D0  +  D3 and D1  +  D3 data, respectively. Additionally, kidney doses obtained from single time point method using a monoexponential curve with the population mean effective half-life, normalized to activities at D0 or D1 or D3 points, were calculated. The accuracy of simplified dosimetry methods was assessed as the percentage difference relative to doses calculated from M1. The major contribution to the absorbed dose estimate comes from the area under the late time portion of the TAC (D1 to infinity). Therefore, information from the late scan (D3) is crucial for the determination of kidney absorbed doses. Single time point method using monoexponential TAC, with the population mean effective half-life normalized to the late data point (48-72 h for kidneys) produces  <10% deviation in the absorbed dose estimation, thus is recommended for clinical use.

Purpose: Peptide receptor radionuclide therapy (PRRT) is mostly administered using a fixed injected activity (IA) per cycle. This empiric regime results in highly variable absorbed doses to the critical organs and undertreatment of the majority of patients. We conceived a personalized PRRT protocol in which the IA is adjusted to deliver a prescribed absorbed dose to the kidney, with the aim to safely increase tumour irradiation. We herein report on the initial results of our prospective study of personalized PRRT, the P-PRRT Trial (NCT02754297)., Methods: PRRT-naïve patients with progressive and/or symptomatic neuroendocrine tumour (NET) were scheduled to receive a four-cycle induction course of 177 Lu-octreotate with quantitative SPECT/CT-based dosimetry. The IA was personalized according to the glomerular filtration rate and the body surface area for the first cycle, and according to the prior renal Gy/GBq for the subsequent cycles. The prescribed renal absorbed dose of 23 Gy was reduced by 25-50% in case of significant renal or haematological impairment. Responders were allowed to receive consolidation or maintenance cycles, for each of which 6 Gy to the kidney were prescribed. We simulated the empiric PRRT regime by fixing the IA at 7.4 GBq per cycle, with the same percentage reductions as above. Radiological, molecular imaging, biochemical, and quality of life responses, as well as safety, were assessed., Results: Fifty-two patients underwent 171 cycles. In 34 patients who completed the induction course, a median cumulative IA of 36.1 (range, 6.3-78.6) GBq was administered, and the median cumulative kidney and maximum tumour absorbed doses were 22.1 (range, 8.3-24.3) Gy and 185.7 (range: 15.2-443.1) Gy respectively. Compared with the simulated fixed-IA induction regime, there was a median 1.26-fold increase (range, 0.47-2.12 fold) in the cumulative maximum tumour absorbed dose, which was higher in 85.3% of patients. In 39 assessable patients, the best objective response was partial response in nine (23.1%), minor response in 14 (35.9%), stable disease in 13 (33.3%) and progressive disease in three patients (7.7%). In particular, 11 of 13 patients (84.6%) with pancreatic NET had partial or minor response. The global health status/quality of life score significantly increased in 50% of patients. Acute and subacute side-effects were all of grade 1 or 2, and the most common were nausea (in 32.7% of patients) and fatigue (in 30.8% of patients) respectively. Subacute grade 3 or 4 toxicities occurred in less than 10% of patients, with the exception of lymphocytopenia in 51.9% of patients, without any clinical consequences however. No patient experienced severe renal toxicity., Conclusions: Personalized PRRT makes it possible to safely increase tumour irradiation in the majority of patients. Our first results indicate a favourable tolerance profile, which appears similar to that of the empiric regime. The response rates are promising, in particular in patients with NET of pancreatic origin.

Purpose: Peptide receptor radionuclide therapy (PRRT) with 177 Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course., Methods: Thirty-six patients underwent 122 fixed-IA 177 Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four-cycle induction course (29.6 ± 2.4 GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2 ± 5.5, 1.3 ± 0.8, and 114 ± 66 Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23 Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle., Results: In the P-PRRT regime, cumulative IA could have been increased to 43.7 ± 16.5 GBq over four induction cycles (10.9 ± 5.0 GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5 ± 2.5, 1.63 ± 0.61, and 163.4 ± 85.9 Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68-2.64-fold; P = 0.0013)., Conclusion: By standardizing the renal absorbed dose delivered during the induction course, P-PRRT has the potential to significantly increase tumour absorbed dose, thus to augment the therapeutic benefit while limiting toxicity.

A 48-year-old Caucasian male patient with newly diagnosed neuroendocrine tumor of the pancreas with multiple liver metastases developed severe and refractory hypercalcemia. Complementary investigations were compatible with humoral hypercalcemia with high parathyroid hormone-related peptide (PTHrP) levels. Hypercalcemia was refractory to medical treatments for more than 2 years. Serum calcium returned to normal values only after 4 cycles of peptide receptor radionuclide therapy with Lu-octreotate, with concomitant reduction of PTHrP level and tumor regression. The use of radionuclide therapy could be an option for the management of severe humoral hypercalcemia in patients with inoperable metastatic pancreatic neuroendocrine tumor.

Purpose: To create an accurate map of the distribution of radiation dose deposition in healthy and target tissues during radionuclide therapy., Methods: Serial quantitative SPECT∕CT images were acquired at 4, 24, and 72 h for 28 (177)Lu-octreotate peptide receptor radionuclide therapy (PRRT) administrations in 17 patients with advanced neuroendocrine tumors. Deformable image registration was combined with an in-house programming algorithm to interpolate pharmacokinetic uptake and clearance at a voxel level. The resultant cumulated activity image series are comprised of values representing the total number of decays within each voxel's volume. For PRRT, cumulated activity was translated to absorbed dose based on Monte Carlo-determined voxel S-values at a combination of long and short ranges. These dosimetric image sets were compared for mean radiation absorbed dose to at-risk organs using a conventional MIRD protocol (OLINDA 1.1)., Results: Absorbed dose values to solid organs (liver, kidneys, and spleen) were within 10% using both techniques. Dose estimates to marrow were greater using the voxelized protocol, attributed to the software incorporating crossfire effect from nearby tumor volumes., Conclusions: The technique presented offers an efficient, automated tool for PRRT dosimetry based on serial post-therapy imaging. Following retrospective analysis, this method of high-resolution dosimetry may allow physicians to prescribe activity based on required dose to tumor volume or radiation limits to healthy tissue in individual patients.

Purpose: Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of (68)Ga-DOTA-octreotate., Methods: Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on (68)Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion., Results: There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake., Conclusion: Our results suggest that tumour sequestration of (68)Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues.

Purpose: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). Methods: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. Results: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57–66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. Conclusion: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. Trial registration: NCT02592707. Registered October 30, 2015. [ABSTRACT FROM AUTHOR]

Purpose: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. Methods: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 μg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. Results: Median cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment‑related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3–99.4), and overall response rate was 21.1% (95% CI: 9.6–37.3). Conclusion: [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. Trial registration: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015. [ABSTRACT FROM AUTHOR]

Purpose: Peptide receptor radionuclide therapy (PRRT) is mostly administered using a fixed injected activity (IA) per cycle. This empiric regime results in highly variable absorbed doses to the critical organs and undertreatment of the majority of patients. We conceived a personalized PRRT protocol in which the IA is adjusted to deliver a prescribed absorbed dose to the kidney, with the aim to safely increase tumour irradiation. We herein report on the initial results of our prospective study of personalized PRRT, the P-PRRT Trial (NCT02754297).Methods: PRRT-naïve patients with progressive and/or symptomatic neuroendocrine tumour (NET) were scheduled to receive a four-cycle induction course of 177Lu-octreotate with quantitative SPECT/CT-based dosimetry. The IA was personalized according to the glomerular filtration rate and the body surface area for the first cycle, and according to the prior renal Gy/GBq for the subsequent cycles. The prescribed renal absorbed dose of 23 Gy was reduced by 25-50% in case of significant renal or haematological impairment. Responders were allowed to receive consolidation or maintenance cycles, for each of which 6 Gy to the kidney were prescribed. We simulated the empiric PRRT regime by fixing the IA at 7.4 GBq per cycle, with the same percentage reductions as above. Radiological, molecular imaging, biochemical, and quality of life responses, as well as safety, were assessed.Results: Fifty-two patients underwent 171 cycles. In 34 patients who completed the induction course, a median cumulative IA of 36.1 (range, 6.3-78.6) GBq was administered, and the median cumulative kidney and maximum tumour absorbed doses were 22.1 (range, 8.3-24.3) Gy and 185.7 (range: 15.2-443.1) Gy respectively. Compared with the simulated fixed-IA induction regime, there was a median 1.26-fold increase (range, 0.47-2.12 fold) in the cumulative maximum tumour absorbed dose, which was higher in 85.3% of patients. In 39 assessable patients, the best objective response was partial response in nine (23.1%), minor response in 14 (35.9%), stable disease in 13 (33.3%) and progressive disease in three patients (7.7%). In particular, 11 of 13 patients (84.6%) with pancreatic NET had partial or minor response. The global health status/quality of life score significantly increased in 50% of patients. Acute and subacute side-effects were all of grade 1 or 2, and the most common were nausea (in 32.7% of patients) and fatigue (in 30.8% of patients) respectively. Subacute grade 3 or 4 toxicities occurred in less than 10% of patients, with the exception of lymphocytopenia in 51.9% of patients, without any clinical consequences however. No patient experienced severe renal toxicity.Conclusions: Personalized PRRT makes it possible to safely increase tumour irradiation in the majority of patients. Our first results indicate a favourable tolerance profile, which appears similar to that of the empiric regime. The response rates are promising, in particular in patients with NET of pancreatic origin. [ABSTRACT FROM AUTHOR]

Purpose: Peptide receptor radionuclide therapy (PRRT) with Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course. Methods: Thirty-six patients underwent 122 fixed-IA Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four-cycle induction course (29.6 ± 2.4 GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2 ± 5.5, 1.3 ± 0.8, and 114 ± 66 Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23 Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle. Results: In the P-PRRT regime, cumulative IA could have been increased to 43.7 ± 16.5 GBq over four induction cycles (10.9 ± 5.0 GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5 ± 2.5, 1.63 ± 0.61, and 163.4 ± 85.9 Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68-2.64-fold; P = 0.0013). Conclusion: By standardizing the renal absorbed dose delivered during the induction course, P-PRRT has the potential to significantly increase tumour absorbed dose, thus to augment the therapeutic benefit while limiting toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of Ga-DOTA-octreotate. Methods: Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion. Results: There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake. Conclusion: Our results suggest that tumour sequestration of Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues. [ABSTRACT FROM AUTHOR]

177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267). [ABSTRACT FROM AUTHOR]

Simple Summary: The peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination of LuTate with chemotherapy improves its objective response in NET patients, and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. Using multiple NET and non-NET cell lines, we examined the SSTR2 expression for up to 7 days after exposure to drugs and its effect on LuTate uptake and cell proliferation. We report that the exposure to varying doses of chemotherapeutic drugs such as temozolomide for 24 h or 5 days results in upregulation of SSTR2 receptors between 3–7 days. This effect is more pronounced in low SSTR2 expressing BON-1 cells than in high SSTR2 expressing NCI-H727 or non-NET cancer or non-cancer cells. Thus, a properly-timed pre-treatment with low doses of chemotherapy could improve therapeutic efficacy of LuTate in NET patients. The peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for different types of neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination with chemotherapy improves objective response to LuTate in NET patients and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. The NET cell lines with low (BON-1) or relatively high (NCI-H727) SSTR2-expression levels, and non-NET cancer and normal cells were treated with chemotherapeutic drugs and assessed for upregulation of SSTR2. We report that an exposure to low or high doses of drugs, such as temozolomide for 24 h or 5 day results in upregulation of SSTR2 between 3–7 days, increased LuTate uptake and decreased rate of cell proliferation. This effect is at the level of SSTR2-mRNA and is more pronounced in low SSTR2 expressing BON-1 than in high SSTR2 expressing NCI-H727 or non-NET cancer or normal cells. Thus, a properly timed pre-treatment with low-dose chemotherapy could not only improve therapeutic efficacy of LuTate in NET patients who are presently eligible for PRRT, but also allow PRRT to be administered to patients with low SSTR-expressing NETs, who would otherwise not respond to this modality because of insufficient radiation delivery. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]