177Lu-DOTATATE Peptide Receptor Radionuclide Therapy Research Articles

Metastatic Malignant Paraganglioma of Rare Sites Failed on Conventional Treatments Demonstrating Beneficial Response to 177Lu-DOTATATE PRRT

AbstractThe incidence of paraganglioma (PGL) is rising due to better imaging modalities employed for evaluating incidentaloma and surveillance of the asymptomatic carriers. Benign and malignant PGLs often cannot be reliably diagnosed on histology alone, and the documentation of metastases is important in the diagnosis of malignancy. Advancement in genomics has improved our understanding of PGL. 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) scan shows a significant superior detection rate compared with other conventional functional and anatomical imaging modalities, can detect rare sites of primary disease in PGL, and also aids in patient selection for peptide receptor radionuclide therapy (PRRT). PRRT is increasingly used in metastatic setting with good symptomatic and biochemical response and disease stabilization in metastatic PGL patients. We present a series of three patients with PGLs located in rare primary sites (sigmoid colon, urinary bladder, and carotid body space), which showed recurrence of disease on conventional treatments and developed metastatic disease in the lymph nodes, liver, skeleton, and lungs. PRRT with 177Lu-DOTATATE achieved symptom control, favorable biochemical and imaging responses, and increased progression-free and overall survival rate in the described patients.

177 Lu-DOTATATE PRRT Safety and Organ-at-Risk Dosimetry in Patients With Gastroenteropancreatic Neuroendocrine Tumors : Data From the Prospective Phase 2 LUMEN Study.

The aim of this study was to assess the association among toxicity, dosimetry of organs-at-risk, and disease progression in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with 177 Lu-DOTATATE. Thirty-seven patients with GEP-NETs underwent 177 Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in a single-arm, prospective, phase 2 study, where patients were followed up with blood tests, isotopic glomerular filtration rate (iGFR), and imaging examinations (CT/MRI and PET) every 6 months until disease progression. Adverse events (AEs) graded per CTCAEv4.03 and occurring during treatment were collected and followed up until resolution. Dosimetry, including biologically effective doses (BEDs) to kidneys, BED to bone marrow, and absorbed dose (AD) to spleen, was performed after each PRRT cycle. Statistical analyses explored associations among dosimetry, toxicity, and patient progression free-survival. The most common AEs were anemia and lymphopenia (65%), followed by thrombocytopenia and fatigue (each 51%), alopecia (46%), and nausea (41%). The most common grade ≥3 AE was lymphopenia (43%). There was no grade ≥3 nephrotoxicity. The median iGFR % decrease was 11% ( P < 0.001), at a median follow-up of 23 months. iGFR %decrease and renal BED did not correlate (Spearman ρ = -0.09). Similarly, no significant association was found between bone marrow BED or spleen AD and the grades of hematological toxicities. We observed no association between progression free-survival and either the decline of renal function or the occurrence of hematological toxicities during PRRT. This study confirms the safety profile of 177 Lu-DOTATATE PRRT in patients with GEP-NETs irrespective of the dosimetry of organs at risk. Kidney, bone marrow, and spleen dosimetry measures were not associated with renal or hematological toxicity.

Repeat Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors: A NET Center of Excellence Experience.

The available data for the safety and efficacy of repeat peptide receptor radionuclide therapy (PRRT) are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients with neuroendocrine tumors (NETs) at our NET center of excellence. We used our single-center longitudinal NET registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either 177Lu DOTATATE or 90Y DOTATOC) and following radiographic disease progression were re-treated with a second course of PRRT (PRRT 2). We reviewed patient, tumor and treatment characteristics, objective response rates, and toxicities after PRRT 1 and PRRT 2. A total of 11 patients were included in the analysis. 45.5% (5/11) of patients received 177Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) of patients received 90Y DOTATOC PRRT for PRRT1. At first restaging scan after PRRT2 (3-6months), 18.2% (2/11), 36.4% (4/11), and 27.3% (3/11) of patients had PR, SD, and PD, respectively; 2/11 patients (18.2%) died before the first restaging scan. Therefore, 5/11 (45.5%) patients were noted to have disease progression. Median PFS for PRRT1 was 25.4months and median PFS for PRRT2 was 13.1months (p = 0.0001). We did not find a statistically significant difference between the occurrence of short and long-term hematological toxicities as well as renal toxicity after PRRT1 and PRRT2. We show that repeat PRRT may benefit select patients and have an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1.

Theranostics in Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are rare tumors that develop from cells of the neuroendocrine system and can originate in multiple organs and tissues such as the bowels, pancreas, adrenal glands, ganglia, thyroid, and lungs. This review will focus on gastroenteropancreatic NETs (more commonly called NETs) characterized by frequent somatostatin receptor (SSTR) overexpression and pheochromocytomas/paragangliomas (PPGLs), which typically overexpress norepinephrine transporter. Advancements in SSTR-targeted imaging and treatment have revolutionized the management of patients with NETs. This comprehensive review delves into the current practice, discussing the use of the various Food and Drug Administration-approved SSTR-agonist positron emission tomography tracers and the predictive imaging biomarkers, and elaborating on 177Lu-DOTATATE peptide receptor radionuclide therapy including the evolving areas of posttherapy imaging practices and peptide receptor radionuclide therapy retreatment. SSTR-targeted imaging and therapy can also be used in patients with PPGL; however, this patient population has demonstrated the best outcomes from norepinephrine transporter-targeted therapy with 131I-metaiodobenzylguanidine. Metaiodobenzylguanidine theranostics for PPGL will be discussed, noting that in 2024 it became commercially unavailable in the United States. Therefore, the use and reported success of SSTR theranostics for PPGL will also be explored.

Visual and whole-body quantitative analyses of 68Ga-DOTATATE PET/CT for prognosis of outcome after PRRT with 177Lu-DOTATATE.

Somatostatin receptors (SSTR) represent an ideal target for nuclear theranostics applications in neuroendocrine tumors (NET). Studies suggest that high uptake on SSTR-PET is associated with response to SSTR peptide receptor radionuclide therapy (PRRT). The purpose of this study was to evaluate the role of baseline whole-body (WB) 68Ga-DOTATATE PET/CT (SSTR-PET) quantitative parameters, and the presence of NET lesions without uptake on SSTR-PET, as outcome prognosticator in patients with NET treated with PRRT. Patients with NET who underwent at least 4 177Lu-DOTATATE PRRT cycles between 07/2016 and 03/2021 were included in this retrospective analysis if they fulfilled the following inclusion criteria: SSTR-PET within 6months of 1st PRRT cycle, follow-up CT and/or MRI performed > 6months after the 4th cycle of PRRT. The SSTR-PET analysis consisted of a visual and a quantitative analysis done independently by two board-certified physicians. The visual analysis assessed the presence of NET lesions visible on the SSTR-PET co-registered CT. The quantitative analysis consisted in contouring all SSTR-avid lesions on SSTR-PET and extracting WB quantitative parameters: SUVmean (WB-SUVmean), SUVmax of the lesion with highest uptake (H-SUVmax), and tumor volume (WB-TV). WB-SSTR-PET parameters and the presence of SSTR-PET-negative lesions were correlated to radiologic response (assessed by RECIST 1.1 criteria) and progression-free survival (PFS). Fisher's exact test, Mann-Whitney's U test and Kaplan-Meier curves with Cox-regression analysis were used for the statistical analysis. Forty patients (F/M: 21/19; 34/40 with gastro-entero-pancreatic (GEP) NET, 6/40 with non-GEP NET) were included in the analysis. The median follow-up period after the 4th PRRT cycle was 25.7months (range 15.2-59.1). Fourteen/40 (35%) patients showed radiologic response (RECIST PR). PFS event was observed in 17/40 (42.5%) patients. Thirteen/40 (32.5%) patients had SSTR-PET-negative lesions at baseline. Higher WB-SUVmean and H-SUVmax were associated with better response (p = 0.015 and 0.005, respectively). The presence of SSTR-PET-negative lesions and lower WB-SUVmean were associated with shorter PFS (p = 0.026 and 0.008, respectively). Visual and quantitative analyses of baseline SSTR-PET can yield valuable information to prognosticate outcomes after 177Lu-DOTATATE PRRT.

Outcome on Mesenteric Mass Response of Small-Intestinal Neuroendocrine Tumors Treated by 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: The MesenLuth Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

A mesenteric mass (MM), characterized by fibrotic reaction, is present in most small-intestinal neuroendocrine tumors (SI-NETs). 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) has shown its efficacy in patients with progressive SI-NETs. However, because of specific tissue characteristics of desmoplastic MMs, we hypothesize that these lesions may be refractory to 177Lu-DOTATATE PRRT. Methods: From the national French Groupe d'étude des Tumeurs Endocrines database, we identified patients with an advanced SI-NET and a MM (≥2 cm with a retractile aspect) of a SI-NET treated by at least 1 course of 177Lu-DOTATATE PRRT. The primary endpoint was a MM objective response rate (ORR) of less than 5%. Secondary endpoints were metabolic response, MM-related safety, and clinical response, as well as MM progression-free survival (PFS) and non-MM PFS. Results: In total, 52 patients were included. The MM ORR was 4% (n = 2), and the non-MM ORR was 8% (n = 4). No patient had a MM metabolic response, and the non-MM metabolic response rate was 12% (n = 6). Among the 26 patients with baseline MM-related symptoms, 46% had a clinical response. Four patients presented with gastrointestinal complications during PRRT. The median MM-related PFS was not reached, and the non-MM PFS was 50.3 mo (95% CI, 38.2-61.7 mo). Conclusion: This study confirms that 177Lu-DOTATATE PRRT does not lead to morphologic response on MMs (ORR < 5%). However, it allows MM stability, with few MM-related side effects, and has a relevant impact on MM-related symptoms.

Prediction of 177Lu-DOTATATE Therapy Outcomes in Neuroendocrine Tumor Patients Using Semi-Automatic Tumor Delineation on 68Ga-DOTATATE PET/CT.

Treatment of metastatic neuroendocrine tumors (NET) with 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) results in favorable response only in a subset of patients. We investigated the prognostic value of quantitative pre-treatment semi-automatic 68Ga-DOTATATE PET/CT analysis in NET patients treated with PRRT. The medical records of 94 NET patients who received at least one cycle of PRRT at a single institution were retrospectively reviewed. On each pre-treatment 68Ga-DOTATATE PET/CT, the total tumor volume (TTV), maximum tumor standardized uptake value for the patient (SUVmax), and average uptake in the lesion with the lowest radiotracer uptake (SUVmin) were determined with a semi-automatic tumor delineation method. Progression-free survival (PFS) and overall survival (OS) among the patients were compared based on optimal cutoff values for the imaging parameters. On Kaplan-Meier analysis and univariate Cox regression, significantly shorter PFS was observed in patients with lower SUVmax, lower SUVmin, and higher TTV. On multivariate Cox regression, lower SUVmin and higher TTV remained predictive of shorter PFS. Only higher TTV was found to be predictive of shorter OS on Kaplan-Meier and Cox regression analyses. In a post hoc Kaplan-Meier analysis, patients with at least one high-risk feature (low SUVmin or high TTV) showed shorter PFS and OS, which may be the most convenient parameter to measure in clinical practice. The tumor volume and lowest lesion uptake on 68Ga-DOTATATE PET/CT can predict disease progression following PRRT in NET patients, with the former also predictive of overall survival. NET patients at risk for poor outcomes following PRRT can be identified with semi-automated quantitative analysis of 68Ga-DOTATATE PET/CT.

PP492 177Lu-DOTATATE peptide receptor radionuclide therapy in patients with advanced neuroendocrine tumors: Asian retrospective analysis

PP492 177Lu-DOTATATE peptide receptor radionuclide therapy in patients with advanced neuroendocrine tumors: Asian retrospective analysis

177Lu-DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) in Metastatic/inoperable phaeochromocytomas and paragangliomas and focus on the impact of genetic variations in SDHx mutation on treatment outcomes - A single centre retrospective analysis of experience at an ENETS Centre of Excellence

¹⁷⁷Lu-DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) in Metastatic/inoperable phaeochromocytomas and paragangliomas and focus on the impact of genetic variations in SDHx mutation on treatment outcomes - A single centre retrospective analysis of experience at an ENETS Centre of Excellence

Impact of Single-Time-Point Estimates of 177Lu-PRRT Absorbed Doses on Patient Management: Validation of a Trained Multiple-Linear-Regression Model in 159 Patients and 477 Therapy Cycles.

Dosimetry after 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) enables estimation of radiation doses absorbed by normal organs and target lesions. This process is time-consuming and requires multiple posttreatment studies on several subsequent days. In a previous study, we described a newly developed multiple-linear-regression model to predict absorbed doses (ADs) from a single-time-point (STP) posttreatment study acquired 168 h after the first infusion and 24 h after the following ones, with similar results to the standard multiple-time-point (MTP) protocol. The present study aimed to validate this model in a large patient cohort and to assess whether STP dosimetry affects patient management decisions compared with our MTP protocol. Methods: Quantitative 177Lu-DOTATATE SPECT/CT post-PRRT data from 159 consecutive patients (172 therapies, 477 therapy cycles) were retrospectively analyzed. ADs obtained from an STP model were compared with those obtained using an MTP model. We evaluated the impact of the STP model on the decision on whether PRRT should be stopped because of an expected kidney AD exceeding the safety threshold. We hypothesized that patient management based on the STP model does not differ from that based on the MTP model in at least 90% of the cases. Results: There was no difference in management decisions between the MTP and STP models in 170 of 172 therapies (98.8%). A Fisher χ2 test for combined probabilities produced a composite P value of 0.0003. Mean cumulative AD relative differences between the STP and MTP models were 0.8% ± 8.0%, -7.7% ± 4.8%, 0.0% ± 11.4%, -2.8% ± 6.3%, and -2.1% ± 18.4% for kidneys, bone marrow, liver, spleen, and tumors, respectively (Pearson r = 0.99 for all), for patients who underwent 4 therapy cycles. Similar results were obtained with fewer therapy cycles. Conclusion: Estimated radiation ADs and patient management decisions were similar with the STP and MTP models. The STP model can simplify the dosimetry process while also reducing scanner and staff time and improving patient comfort.

Upregulation of Somatostatin Receptor Type 2 Improves 177Lu-DOTATATE Therapy in Receptor-Deficient Pancreatic Neuroendocrine Tumor Model.

Pancreatic neuroendocrine tumors (PNET) express high levels of somatostatin receptor type 2 (SSTR2), a unique target for both tumor imaging and therapy. This surface expression is lost in metastatic high-grade PNETs, making patients ineligible for SSTR2-targeted 177 Lutetium (Lu)-DOTATATE peptide receptor radionuclide therapy (PRRT), and represents an unmet clinical need. Here, we aimed to restore SSTR2 expression through the reversal of inhibitory epigenetic gene silencing to improve tumor responsiveness to PRRT. We first assessed human SSTR2 promoter methylation and expression levels in 96 patient samples. We then used three NET cell lines (QGP-1, BON-1, GOT-1) with variable SSTR2 expression profiles for functional in vitro studies using histone deacetylase inhibitors (HDACi). Finally, the QGP-1 xenograft mouse model, with low basal SSTR2 expression, was used to assess the therapeutic efficacy of combined HDACi and 177Lu-DOTATATE therapies. We confirm that SSTR expression is decreased and correlates with SSTR2 promoter methylation in patients with high-grade NETs. When exposed to HDACis, SSTR2 surface expression is increased in three NET cell lines in vitro. In an in vivo PNET xenograft model with low basal SSTR2 expression, our studies demonstrate significantly higher tumor uptake of SSTR2-targeted 177Lu-DOTATATE in animals pretreated with HDACis compared with controls. For the first time, we show that this higher tumor uptake results in significant antitumor response when compared with standard PRRT alone. These preclinical results provide a rationale for utilizing HDACi pretreatment to improve targeted radionuclide therapy in patients with SSTR2-negative, metastatic PNETs.

A case of frequent hypoglycemic attacks successfully controlled with capecitabine plus temozolomide and 177Lu-DOTATATE peptide receptor radionuclide therapy in a patient with recurrent pancreatic insulinoma.

A 59-year-old woman with metastatic pancreatic insulinoma, having undergone several treatment regimens including sunitinib, everolimus, lanreotide and streptozocin plus 5-fluorouracil, was admitted to our hospital because of frequent hypoglycemic attacks. These were refractory to medical treatment using diazoxide and required frequent daily intravenous glucose infusions. She was started on capecitabine and temozolomide (CAPTEM), followed by initiation of 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT). The frequency of hypoglycemic attacks decreased after treatment began and she was discharged on day 58 post-admission, without requiring daily glucose infusions. CAPTEM and PRRT were continued without any major adverse events. Computed tomography revealed shrinkage of primary and metastatic lesions, an anti-tumor effect that continued 8months after treatment was initiated. Hypoglycemic attacks caused by insulinomas are often refractory to conventional therapy; however, combination treatment using CAPTEM and PRRT has demonstrated a positive and significant response, successfully restoring glycemic control.

Accuracy and uncertainty analysis of reduced time point imaging effect on time-integrated activity for 177Lu-DOTATATE PRRT in patients and clinically realistic simulations

BackgroundDosimetry promises many advantages for radiopharmaceutical therapies but repeat post-therapy imaging for dosimetry can burden both patients and clinics. Recent applications of reduced time point imaging for time-integrated activity (TIA) determination for internal dosimetry following 177Lu-DOTATATE peptide receptor radionuclide therapy have shown promising results that allow for the simplification of patient-specific dosimetry. However, factors such as scheduling can lead to sub-optimal imaging time points, but the resulting impact on dosimetry accuracy is still under investigation. We use four-time point 177Lu SPECT/CT data for a cohort of patients treated at our clinic to perform a comprehensive analysis of the error and variability in time-integrated activity when reduced time point methods with various combinations of sampling points are employed.MethodsThe study includes 28 patients with gastroenteropancreatic neuroendocrine tumors who underwent post-therapy SPECT/CT imaging at approximately 4, 24, 96, and 168 h post-therapy (p.t.) following the first cycle of 177Lu-DOTATATE. The healthy liver, left/right kidney, spleen and up to 5 index tumors were delineated for each patient. Time-activity curves were fit with either monoexponential or biexponential functions for each structure, based on the Akaike information criterion. This fitting was performed using all 4 time points as a reference and various combinations of 2 and 3 time points to determine optimal imaging schedules and associated errors. 2 commonly used methods of single time point (STP) TIA estimation are also evaluated. A simulation study was also performed with data generated by sampling curve fit parameters from log-normal distributions derived from the clinical data and adding realistic measurement noise to sampled activities. For both clinical and simulation studies, error and variability in TIA estimates were estimated with various sampling schedules.ResultsThe optimal post-therapy imaging time period for STP estimates of TIA was found to be 3–5 days (71–126 h) p.t. for tumor and organs, with one exception of 6–8 days (144–194 h) p.t. for spleen with one STP approach. At the optimal time point, STP estimates give mean percent errors (MPE) within ± 5% and SD < 9% across all structures with largest magnitude error for kidney TIA (MPE = − 4.1%) and highest variability also for kidney TIA (SD = 8.4%). The optimal sampling schedule for 2TP estimates of TIA is 1–2 days (21–52 h) p.t. followed by 3–5 days (71–126 h) p.t. for kidney, tumor, and spleen. Using the optimal sampling schedule, the largest magnitude MPE for 2TP estimates is 1.2% for spleen and highest variability is in tumor with SD = 5.8%. The optimal sampling schedule for 3TP estimates of TIA is 1–2 days (21–52 h) p.t. followed by 3–5 days (71–126 h) p.t. and 6–8 days (144–194 h) p.t. for all structures. Using the optimal sampling schedule, the largest magnitude MPE for 3TP estimates is 2.5% for spleen and highest variability is in tumor with SD = 2.1%. Simulated patient results corroborate these findings with similar optimal sampling schedules and errors. Many sub-optimal reduced time point sampling schedules also exhibit low error and variability.ConclusionsWe show that reduced time point methods can be used to achieve acceptable average TIA errors over a wide range of imaging time points and sampling schedules while maintaining low uncertainty. This information can improve the feasibility of dosimetry for 177Lu-DOTATATE and elucidate the uncertainty associated with non-ideal conditions.

177 Lu-DOTATATE Therapy in a Case of Castrate-Resistant Prostate Cancer With Neuroendocrine Differentiation.

An 84-year-old man with prostate cancer with neuroendocrine differentiation underwent PET/CT for staging. 68 Ga-prostate-specific membrane antigen PET/CT did not show significant abnormal tracer accumulation, whereas 18 F-OC ( 18 F-AlF-NOTA-octreotide) PET/CT showed elevated tracer uptake at multiple sites throughout the body. Therefore, the patient opted to receive 1 cycle of 177 Lu-DOTATATE peptide receptor radionuclide therapy with a dose of 200 mCi. Encouragingly, radiographic tumor remission and improvement of clinical symptoms were observed after only 1 cycle of treatment.

Recombinant α1-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a 177Lu-DOTATATE Mouse Radiation Model.

177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although 177Lu-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. α1-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M's renal protective effect in a mouse 177Lu-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-177Lu-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with 177Lu-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with 177Lu-DOTATATE.

177Lu-DOTATATE Theranostics: Predicting Renal Dosimetry From Pretherapy 68Ga-DOTATATE PET and Clinical Biomarkers.

Pretreatment predictions of absorbed doses can be especially valuable for patient selection and dosimetry-guided individualization of radiopharmaceutical therapy. Our goal was to build regression models using pretherapy 68Ga-DOTATATE PET uptake data and other baseline clinical factors/biomarkers to predict renal absorbed dose delivered by 177Lu-DOTATATE peptide receptor radionuclide therapy (177Lu-PRRT) for neuroendocrine tumors. We explore the combination of biomarkers and 68Ga PET uptake metrics, hypothesizing that they will improve predictive power over univariable regression. Pretherapy 68Ga-DOTATATE PET/CTs were analyzed for 25 patients (50 kidneys) who also underwent quantitative 177Lu SPECT/CT imaging at approximately 4, 24, 96, and 168 hours after cycle 1 of 177Lu-PRRT. Kidneys were contoured on the CT of the PET/CT and SPECT/CT using validated deep learning-based tools. Dosimetry was performed by coupling the multi-time point SPECT/CT images with an in-house Monte Carlo code. Pretherapy renal PET SUV metrics, activity concentration per injected activity (Bq/mL/MBq), and other baseline clinical factors/biomarkers were investigated as predictors of the 177Lu SPECT/CT-derived mean absorbed dose per injected activity to the kidneys using univariable and bivariable models. Leave-one-out cross-validation (LOOCV) was used to estimate model performance using root mean squared error and absolute percent error in predicted renal absorbed dose including mean absolute percent error (MAPE) and associated standard deviation (SD). The median therapy-delivered renal dose was 0.5 Gy/GBq (range, 0.2-1.0 Gy/GBq). In LOOCV of univariable models, PET uptake (Bq/mL/MBq) performs best with MAPE of 18.0% (SD = 13.3%), and estimated glomerular filtration rate (eGFR) gives an MAPE of 28.5% (SD = 19.2%). Bivariable regression with both PET uptake and eGFR gives LOOCV MAPE of 17.3% (SD = 11.8%), indicating minimal improvement over univariable models. Pretherapy 68Ga-DOTATATE PET renal uptake can be used to predict post-177Lu-PRRT SPECT-derived mean absorbed dose to the kidneys with accuracy within 18%, on average. Compared with PET uptake alone, including eGFR in the same model to account for patient-specific kinetics did not improve predictive power. Following further validation of these preliminary findings in an independent cohort, predictions using renal PET uptake can be used in the clinic for patient selection and individualization of treatment before initiating the first cycle of PRRT.

The efficacy, toxicity and survival of salvage retreatment PRRT with 177Lu-DOTATATE in patients with progressive NET following initial course of PRRT.

To evaluate the efficacy, toxicity and survival of salvage peptide receptor radionuclide therapy (PRRT) with indigenous, direct-route 177Lu-labelled-DOTATATE in metastatic Nueroendocrine tumor (NET) patients who showed an objective response or disease stabilization following initial course of 177Lu-DOTATATE PRRT cycles and eventually developed progressive disease after a time-interval of more than 1 year; the variables influencing survival and response of salvage PRRT were also examined. A total of 26 progressive metastatic NET patients who received salvage PRRT with indigenous 177Lu-DOTATATE, were evaluated. Response was assessed under three broad categories as clinical symptomatic, biochemical and imaging (both molecular and morphological imaging). The Kaplan-Meier product-limit method was used to calculate progression-free survival (PFS) and overall survival (OS). Toxicity of salvage PRRT was evaluated by NCI-CTCAE v. 5.0 criteria (included complete blood counts, renal and liver function tests). Association between various variables and response and survival were analyzed using the χ2 test. Out of the 26 patients, the complete follow-up data were not available for four patients, where only survival information was available. Thus, a total of 22 patients (median age: 55 years, range: 38-68 years, 12 men and 10 women) were included and analyzed retrospectively in study. The cumulative dose of initial course of PRRT (I-PRRT) with indigenous 177Lu-DOTATATE ranged from 800 mCi (29.6 GBq) to 1231 mCi (45.54 GBq) per patient {mean administered cumulative dose of 964 mCi (35.66 GBq) per patient}, and the salvage PRRT with indigenous 177Lu-DOTATATE comprised of a mean dose of 170 mCi (6.29GBq) per patient. The disease control rate of 68.1%, 77.3%, 63.6% and 63.6% were observed after salvage PRRT on clinical symptomatic, biochemical, molecular and morphological imaging response respectively. The median PFS after salvage PRRT was 17 months. The median OS was not attained after I-PRRT (OS-i) and salvage PRRT (OS-s). Estimated OS-i rate was 68% at 108 months and OS-s rate was 82% at 18 months. None of the patients developed Grade 3/4 hematotoxicity, nephrotoxicity and hepatotoxicity or AML/MDS after I-PRRT and salvage PRRT at median follow-up of 72 months and 12 months respectively. The highest level of toxicity was Grade 2 [seen as reversible anemia, thrombocytopenia and nephrotoxicity in 3 (13.5%), 1 (4.5%) and 2 patients (9%) respectively]. The significant p-value was not observed for any variable association. With limited therapeutic options available for progressive NET after I-PRRT and in the absence of high-grade toxicity after 177Lu-DOTATATE salvage PRRT, retreatment with PRRT may be considered as a relatively safe therapeutic option for these patients. This study examined salvage retreatment PRRT with indigenous "direct-route" 177Lu-DOTATATE and registered its safety and survival benefits, indicating this could be an effective therapeutic option in this clinical setting.

Real-world outcomes in patients with neuroendocrine tumor receiving peptide receptor radionucleotide therapy.

504 Background: (177)Lu-Dotatate, a form of Peptide Receptor Radionuclide Therapy (PRRT), was approved by FDA for treatment of somatostatin-receptor-positive NETs in 2018. Clinical trials prior to the FDA approval of (177)Lu-Dotatate showed favorable outcomes but there is limited published real world outcomes data. Methods: After obtaining IRB approval we retrospectively evaluated the efficacy of (177)Lu-Dotatate PRRT for somatostatin receptor positive gastroenteropancreatic NET patients at University of Kansas Cancer Center between June 2018 and September 2021. Results: A total of 65 patients received PRRT of which 58 completed treatment and 7 are still undergoing therapy. The 58 patients who completed treatment had a median age of 61.5 years, included 24 females and 34 males, and were 86% Caucasian and 12% black. These patients had primarily NETs of small bowel (n=24) and pancreatic (n=14) origin. Pathology showed grades 1 (21), 2 (25), and 3 (4) with a majority of well-differentiated tumors (47). All 4 treatments of PRRT were completed by 43 patients. In the entire cohort, response assessment to PRRT revealed 14 (26.9%) partial response (PR), 31 (59.6%) with stable disease (SD) and 7 (13.5%) with progressive disease (PD). In subset analysis, we found that patients with nonfunctional disease (n=29) had a higher rate of PR 42.3% vs 11.5% (p=0.0147) and higher disease control rate 96% vs 78% (p=0.042) than functional disease (n=29). Patients with nonfunctional disease had a lower PD 3.85% vs 23% (p=0.0147) and 53% vs 65% stable disease than functional disease. The table below shows clinical characteristics of these patients. Conclusions: Our real world outcomes analysis of NET treated with PRRT shows improved PR when compared to the initial clinical trials which is promising for patients. In addition, we found that there was statistically significant improved response rate in patients with non functional tumors which has not been described in literature before. If our study findings are validated in a larger cohort then it may guide patient selection for PRRT therapy in the future.[Table: see text]

Simplified patient-specific renal dosimetry in 177Lu therapy: a proof of concept.

The aim of this proof-of-concept study is to propose a simplified personalized kidney dosimetry procedure in 177Lu peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors and metastatic prostate cancer. It relies on a single quantitative SPECT/CT acquisition and multiple radiometric measurements executed with a collimated external probe, properly directed on kidneys. We conducted a phantom study involving external count-rate measurements in an abdominal phantom setup filled with activity concentrations of 99mTc, reproducing patient-relevant organ effective half-lives occurring in 177Lu PRRT. GATE Monte Carlo (MC) simulations of the experiment, using 99mTc and 177Lu as sources, were performed. Furthermore, we tested this method via MC on a clinical case of 177Lu-DOTATATE PRRT with SPECT/CT images at three time points (2, 20 and 70 hrs), comparing a simplified kidney dosimetry, employing a single SPECT/CT and probe measurements at three time points, with the complete MC dosimetry. The experimentally estimated kidney half-life with background subtraction applied was compatible within 3% with the expected value. The MC simulations of the phantom study, both with 99mTc and 177Lu, confirmed a similar level of accuracy. Concerning the clinical case, the simplified dosimetric method led to a kidney dose estimation compatible with the complete MC dosimetry within 6%, 12% and 2%, using respectively the SPECT/CT at 2, 20 and 70hrs. The proposed simplified procedure provided a satisfactory accuracy and would reduce the imaging required to derive the kidney absorbed dose to a unique quantitative SPECT/CT, with consequent benefits in terms of clinic workflows and patient comfort.

Dosimetric analyses of intra-arterial versus standard intravenous administration of 177Lu-DOTATATE in patients of well differentiated neuroendocrine tumor with liver-dominant metastatic disease.

The aim of the present study was to perform calculation of the absorbed doses to organs at risk and to neuroendocrine tumors and to determine whether hepatic intra-arterial (IA) injection of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) would achieve higher intratumoral concentrations than standard intravenous administration of 177Lu-DOTATATE. 29 patients with Grade I-II, inoperable, metastatic gastro-entero-pancreatic neuroendocrine tumor (GEPNET) were prospectively identified and enrolled for the study. 15 patients of GEPNETs with liver-dominant metastatic disease and less than 3 sites of extrahepatic metastatic disease were administered a single dose of 177Lu-DOTATATE therapy through the selective catheterization of the hepatic artery (IA group). The other 14 patients received a single dose of 177 Lu- DOTATATE through standard intravenous route (IV group). For dosimetry, whole-body γ (anterior and posterior planar acquisitions) and SPECT/CT scans of the abdomen at 2, 24 and 96 h post 177Lu-DOTATATE administration were acquired. Dosimetric calculations were done using the HERMES software. The mean dose per unit activity (DpA) in the liver and tumor lesions in the IA group differed significantly (p < 0.05) but differed insignificantly in spleen and kidneys (p > 05) with the IV group. The mean tumor/non-tumor concentration at 96 h was 76.83 ± 7.9 (range 10.2-251.3) in the IA group whereas it was 25.6 ± 5.9 (Range: 12-55) in the IV group. There was an average threefold increase in tumoral concentration over the standard intravenous group. IA administration of 177Lu-DOTATATE results in higher concentration and absorbed dose in hepatic metastases in patients of GEPNETs as compared to a single dose of PRRT administered through standard IV route, and thus seems to be a powerful tool to improve the efficacy of PRRT. Measurement of the dose received by the tumor lesions and the critical organs is of paramount importance for the prognostication of a radionuclide therapy. Scant data exist on the dosimetric impact of IA administration of the therapy with 177Lu-DOTATATE on the tumors and other organs, and this study would add an impact towards the better treatment outcome in patients of neuroendocrine tumor with liver-dominant metastatic disease.