[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high­dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study.

BACKGROUND: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. METHODS: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. FINDINGS: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. INTERPRETATION: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. FUNDING: Advanced Accelerator Applications, a Novartis Company.

Nanoscale Covalent Organic Framework with Staggered Stacking of Phthalocyanines for Mitochondria-Targeted Photodynamic Therapy.

Phthalocyanine photosensitizers (PSs) have shown promise in fluorescence imaging and photodynamic therapy (PDT) of malignant tumors, but their practical application is limited by the aggregation-induced quenching (AIQ) and inherent photobleaching of PSs. Herein, we report the synthesis of a two-dimensional nanoscale covalent organic framework (nCOF) with staggered (AB) stacking of zinc-phthalocyanines (ZnPc), ZnPc-PI, for fluorescence imaging and mitochondria-targeted PDT. ZnPc-PI isolates and confines ZnPc PSs in the rigid nCOF to reduce AIQ, improve photostability, enhance cellular uptake, and increase the level of reactive oxygen species (ROS) generation via mitochondrial targeting. ZnPc-PI shows efficient tumor accumulation, which allowed precise tumor imaging and nanoparticle tracking. With high cellular uptake and tumor accumulation, intrinsic mitochondrial targeting, and enhanced ROS generation, ZnPc-PI exhibits potent PDT efficacy with >95% tumor growth inhibition on two murine colon cancer models without causing side effects.

Dotatate PET/CT and 225Ac-Dotatate Therapy for Somatostatin Receptor-expressing Metastatic Breast Cancer.

Background Somatostatin receptors, and specifically somatostatin receptor type 2 (SSTR2), have primarily been associated with neuroendocrine tumors and have revolutionized the imaging and therapy of patients with these tumors. SSTR2 is expressed on other tumors at lower prevalence. Purpose To evaluate the potential of SSTR2-targeted imaging and therapy in patients with breast cancer. Materials and Methods In a preclinical experiment, SSTR2 expression was assessed in tissue microarrays of breast cancer samples using H-score analysis. H-scores higher than 50 (0-300 scale) were considered positive. Then, a prospective phase 2 clinical trial of SSTR2-targeted tetraazacyclododecane tetraacetic acid octreotate (Dotatate) PET/CT was performed in participants with biopsy-proven estrogen receptor (ER)-positive breast cancer from January to August 2023. A positive Dotatate PET/CT scan was defined as tumors with a Krenning score of 3 (avidity greater than liver) or 4 (avidity greater than spleen). The proportion of positive scans and the 95% CI were calculated. One participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET/CT result underwent treatment with SSTR2-targeted actinium 225 (225Ac) Dotatate. Results Preclinical microarrays demonstrated that 63 of 123 ER-positive breast cancer tissue samples (51% [95% CI: 42, 60]) but only 22 of 121 ER-negative breast cancer tissue samples (18% [95% CI: 12, 26]) were enriched for SSTR2 (P < .001). Thirty female participants (mean age, 66 years ± 15) with metastatic ER-positive breast cancer were accrued to the phase 2 SSTR2-targeted imaging trial and underwent Dotatate PET/CT. Dotatate PET/CT demonstrated that nine of 30 participants (30% [95% CI: 15, 49]) had tumors with Krenning scores of 3 or 4, indicating strong SSTR2 expression. SSTR2-targeted therapy with alpha-emitting 225Ac-Dotatate resulted in a near complete response in a heavily pretreated participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET result. Conclusion Molecular imaging targeting SSTR2 and radioligand therapy with SSTR2-targeted 225Ac-Dotatate enables a new therapeutic option for patients with metastatic breast cancer. Clinical trial registration no. NCT05880394 © RSNA, 2024 See also the editorial by Lin and Choyke in this issue.

Intra-arterial peptide-receptor radionuclide therapy for neuro-endocrine tumour liver metastases: an in-patient randomised controlled trial (LUTIA).

PURPOSE: Peptide receptor radionuclide therapy (PRRT) using [177Lu]Lu-DOTATATE has been shown to effectively prolong progression free survival in grade 1-2 gastroenteropancreatic neuroendocrine tumours (GEP-NET), but is less efficacious in patients with extensive liver metastases. The aim was to investigate whether tumour uptake in liver metastases can be enhanced by intra-arterial administration of [177Lu]Lu-DOTATATE into the hepatic artery, in order to improve tumour response without increasing toxicity. METHODS: Twenty-seven patients with grade 1-2 GEP-NET, and bi-lobar liver metastases were randomized to receive intra-arterial PRRT in the left or right liver lobe for four consecutive cycles. The contralateral liver lobe and extrahepatic disease were treated via a "second-pass" effect and the contralateral lobe was used as the control lobe. Up to three metastases (> 3 cm) per liver lobe were identified as target lesions at baseline on contrast-enhanced CT. The primary endpoint was the tumour-to-non-tumour (T/N) uptake ratio on the 24 h post-treatment [177Lu]Lu-SPECT/CT after the first cycle. This was calculated for each target lesion in both lobes using the mean uptake. T/N ratios in both lobes were compared using paired-samples t-test. FINDINGS: After the first cycle, a non-significant difference in T/N uptake ratio was observed: T/NIA = 17·4 vs. T/Ncontrol = 16·2 (p = 0·299). The mean increase in T/N was 17% (1·17; 95% CI [1·00; 1·37]). Of all patients, 67% (18/27) showed any increase in T/N ratio after the first cycle. CONCLUSION: Intra-arterial [177Lu]Lu-DOTATATE is safe, but does not lead to a clinically significant increase in tumour uptake.

The cycle effect quantified: reduced tumour uptake in subsequent cycles of [177Lu]Lu-HA-DOTATATE during peptide receptor radionuclide therapy.

BACKGROUND: Clear evidence regarding the effect of reduced tumour accumulation in later peptide receptor radionuclide therapy (PRRT) cycles is lacking. Therefore, we aimed to quantify potential cycle effects for patients treated with [177Lu]Lu-HA-DOTATATE using a population pharmacokinetic (PK) modelling approach. METHODS: A population PK model was developed using imaging data from 48 patients who received multiple cycles of [177Lu]Lu-HA-DOTATATE. The five-compartment model included a central, kidney, spleen, tumour and lumped rest compartment. Tumour volume and continued use of long-acting somatostatin analogues (SSAs) were tested as covariates in the model. In addition, the presence of a cycle effect was evaluated by relating the uptake rate in a specific cycle as a fraction of the (tumour or organ) uptake rate in the first cycle. RESULTS: The final PK model adequately captured observed radioactivity accumulation in kidney, spleen and tumour. A higher tumour volume was identified to increase the tumour uptake rate, where a twofold increase in tumour volume resulted in a 2.3-fold higher uptake rate. Also, continued use of long-acting SSAs significantly reduced the spleen uptake rate (68.4% uptake compared to SSA withdrawal (10.5% RSE)). Lastly, a cycle effect was significantly identified, where tumour uptake rate decreased to 86.9% (5.3% RSE) in the second cycle and even further to 79.7% (5.6% RSE) and 77.6% (6.2% RSE) in the third and fourth cycle, respectively, compared to cycle one. CONCLUSIONS: Using a population PK modelling approach, the cycle effect of reduced tumour uptake in subsequent PRRT cycles was quantified. Our findings implied that downregulation of target receptors is probably not the major cause of the cycle effect, due to a plateau in the decrease of tumour uptake in the fourth cycle.

p53 stabilisation potentiates [177Lu]Lu-DOTATATE treatment in neuroblastoma xenografts.

PURPOSE: Molecular radiotherapy is a treatment modality that is highly suitable for targeting micrometastases and [177Lu]Lu-DOTATATE is currently being explored as a potential novel treatment option for high-risk neuroblastoma. p53 is a key player in the proapoptotic signalling in response to radiation-induced DNA damage and is therefore a potential target for radiosensitisation. METHODS: This study investigated the use of the p53 stabilising peptide VIP116 and [177Lu]Lu-DOTATATE, either alone or in combination, for treatment of neuroblastoma tumour xenografts in mice. Initially, the uptake of [177Lu]Lu-DOTATATE in the tumours was confirmed, and the efficacy of VIP116 as a monotherapy was evaluated. Subsequently, mice with neuroblastoma tumour xenografts were treated with placebo, VIP116, [177Lu]Lu-DOTATATE or a combination of both agents. RESULTS: The results demonstrated that monotherapy with either VIP116 or [177Lu]Lu-DOTATATE significantly prolonged median survival compared to the placebo group (90 and 96.5 days vs. 50.5 days, respectively). Notably, the combination treatment further improved median survival to over 120 days. Furthermore, the combination group exhibited the highest percentage of complete remission, corresponding to a twofold increase compared to the placebo group. Importantly, none of the treatments induced significant nephrotoxicity. Additionally, the therapies affected various molecular targets involved in critical processes such as apoptosis, hypoxia and angiogenesis. CONCLUSION: In conclusion, the combination of VIP116 and [177Lu]Lu-DOTATATE presents a promising novel treatment approach for neuroblastoma. These findings hold potential to advance research efforts towards a potential cure for this vulnerable patient population.

Deep transformer-based personalized dosimetry from SPECT/CT images: a hybrid approach for [177Lu]Lu-DOTATATE radiopharmaceutical therapy.

PURPOSE: Accurate dosimetry is critical for ensuring the safety and efficacy of radiopharmaceutical therapies. In current clinical dosimetry practice, MIRD formalisms are widely employed. However, with the rapid advancement of deep learning (DL) algorithms, there has been an increasing interest in leveraging the calculation speed and automation capabilities for different tasks. We aimed to develop a hybrid transformer-based deep learning (DL) model that incorporates a multiple voxel S-value (MSV) approach for voxel-level dosimetry in [177Lu]Lu-DOTATATE therapy. The goal was to enhance the performance of the model to achieve accuracy levels closely aligned with Monte Carlo (MC) simulations, considered as the standard of reference. We extended our analysis to include MIRD formalisms (SSV and MSV), thereby conducting a comprehensive dosimetry study. METHODS: We used a dataset consisting of 22 patients undergoing up to 4 cycles of [177Lu]Lu-DOTATATE therapy. MC simulations were used to generate reference absorbed dose maps. In addition, MIRD formalism approaches, namely, single S-value (SSV) and MSV techniques, were performed. A UNEt TRansformer (UNETR) DL architecture was trained using five-fold cross-validation to generate MC-based dose maps. Co-registered CT images were fed into the network as input, whereas the difference between MC and MSV (MC-MSV) was set as output. DL results are then integrated to MSV to revive the MC dose maps. Finally, the dose maps generated by MSV, SSV, and DL were quantitatively compared to the MC reference at both voxel level and organ level (organs at risk and lesions). RESULTS: The DL approach showed slightly better performance (voxel relative absolute error (RAE) = 5.28 ± 1.32) compared to MSV (voxel RAE = 5.54 ± 1.4) and outperformed SSV (voxel RAE = 7.8 ± 3.02). Gamma analysis pass rates were 99.0 ± 1.2%, 98.8 ± 1.3%, and 98.7 ± 1.52% for DL, MSV, and SSV approaches, respectively. The computational time for MC was the highest (~2 days for a single-bed SPECT study) compared to MSV, SSV, and DL, whereas the DL-based approach outperformed the other approaches in terms of time efficiency (3 s for a single-bed SPECT). Organ-wise analysis showed absolute percent errors of 1.44 ± 3.05%, 1.18 ± 2.65%, and 1.15 ± 2.5% for SSV, MSV, and DL approaches, respectively, in lesion-absorbed doses. CONCLUSION: A hybrid transformer-based deep learning model was developed for fast and accurate dose map generation, outperforming the MIRD approaches, specifically in heterogenous regions. The model achieved accuracy close to MC gold standard and has potential for clinical implementation for use on large-scale datasets.

Efficacy of Normalising Serum Zinc Level for Patients with Olfactory Dysfunction and Zinc Deficiency.

INTRODUCTION: Zinc deficiency may worsen the severity of olfactory dysfunction; however, the relationship between serum zinc levels and therapeutic effects on olfactory dysfunction remains uncertain. This study investigated the relationship between normalising serum zinc levels and the therapeutic effects on olfactory dysfunction. METHODS: Forty-two patients diagnosed with post-infectious, post-traumatic, and idiopathic olfactory dysfunction, with serum zinc levels <70 µg/dL, were included in the study. All patients were treated with mecobalamin, tokishakuyakusan, and polaprezinc. The patients were divided into 2 groups: the zinc-normalised (≥70 µg/dL) and zinc-deficient (<70 µg/dL) groups, based on their post-treatment serum zinc levels. Olfactory test results were compared in each of the 2 groups. RESULTS: The patients were treated for a median of 133 days. The zinc-normalised group had significantly better results in all olfactory tests (detection/recognition thresholds of the T&T olfactometer, odour identification test (Open Essence), Visual Analogue Scale for olfactory dysfunction, and self-administered odour questionnaire). In contrast, only the self-administered odour questionnaire showed a significant improvement in the zinc-deficient group, with no significant differences observed in the other olfactory tests. When comparing the changes in the olfactory test scores between the 2 groups, significant differences were observed in the detection/recognition thresholds of the T&T olfactometer test and Open Essence results. CONCLUSION: These findings suggest that patients with olfactory dysfunction may have difficulty improving their olfactory function if they also have zinc deficiency. Furthermore, normalisation of zinc deficiency may contribute to the improvement of olfactory dysfunction with general treatment.

Bioactive Bismuth Compounds: Is Their Toxicity a Barrier to Therapeutic Use?

Bismuth compounds are considered relatively non-toxic, with their low solubility in aqueous solutions (e.g., biological fluids) being the major contributing factor to this property. Bismuth derivatives are widely used for the treatment of peptic ulcers, functional dyspepsia, and chronic gastritis. Moreover, the properties of bismuth compounds have also been extensively explored in two main fields of action: antimicrobial and anticancer. Despite the clinical interest of bismuth-based drugs, several side effects have also been reported. In fact, excessive acute ingestion of bismuth, or abuse for an extended period of time, can lead to toxicity. However, evidence has demonstrated that the discontinuation of these compounds usually reverses their toxic effects. Notwithstanding, the continuously growing use of bismuth products suggests that it is indeed part of our environment and our daily lives, which urges a more in-depth review and investigation into its possible undesired activities. Therefore, this review aims to update the pharmaco-toxicological properties of bismuth compounds. A special focus will be given to in vitro, in vivo, and clinical studies exploring their toxicity.

The effect of long-acting somatostatin analogues on the uptake of [177Lu]Lu-HA-DOTATATE.

PURPOSE: According to IAEA/EANM/SNMMI guidelines, long-acting somatostatin analogues (LA-SSAs) should be discontinued 4-6 weeks prior to peptide receptor radionuclide therapy (PRRT) to prevent somatostatin receptor saturation. The aim of this study was to determine the effect of continued use of long-acting SSAs during PRRT on the uptake of [177Lu]Lu-HA-DOTATATE on SPECT/CT. METHODS: Consecutive patients with neuroendocrine tumours who were treated with PRRT receiving 7.4 GBq of [177Lu]Lu-HA-DOTATATE were included. Patients were divided into 3 groups: (1) control (LA-SSA stopped > 6 weeks prior to PRRT), or continued treatment with (2) long-acting octreotide < 6 weeks prior to PRRT, or (3) long-acting lanreotide < 6 weeks prior to PRRT. The uptake of [177Lu]Lu-HA-DOTATATE was quantified in healthy tissues (spleen, liver, kidneys, bone marrow) and tumour lesions on SPECT/CT performed 24 h after PRRT. A Mann-Whitney U test was used to determine differences in uptake between the long-acting octreotide and long-acting lanreotide groups compared to the control group. RESULTS: Forty-two patients with 135 cycles of PRRT were included: 28 with lanreotide, 50 with octreotide, and 57 cycles without LA-SSAs. Uptake of [177Lu]Lu-HA-DOTATATE was significantly decreased in liver parenchyma in patients with lanreotide (p < 0.001) and in the spleen in patients with either octreotide or lanreotide (both p < 0.001). No differences were observed for uptake in kidneys, bone marrow, and blood pool. Uptake of [177Lu]Lu-HA-DOTATATE in tumours was the same in patients with lanreotide compared to the control (p = 0.862) and in patients with octreotide compared to the control (p = 0.201), independent of tumour location. CONCLUSION: Long-acting octreotide and lanreotide do not interfere with the uptake of [177Lu]Lu-HA-DOTATATE in tumour lesions 24 h post-injection. Uptake in healthy liver parenchyma significantly decreases after lanreotide administration prior to PRRT, while uptake in healthy spleen tissue significantly decreases with both octreotide and lanreotide administration.

The role of quantitative tumor burden based on [68 Ga]Ga-DOTA-NOC PET/CT in well-differentiated neuroendocrine tumors: beyond prognosis.

PURPOSE: We aimed to elucidate the role of quantitative tumor burden based on PET/CT of somatostatin receptors in well-differentiated neuroendocrine tumors (NETs). METHODS: This study enrolled patients with [68 Ga]Ga-DOTA-NOC PET/CT-positive advanced NETs who did not receive medical treatment prior to PET/CT. Tumor burden was calculated using methods based on the background threshold and relative fixed threshold values (30%, 40%, and 50%). The prognostic value of the measured tumor burden in reference to overall survival (OS) and progression-free survival (PFS) on treatment with octreotide long-acting repeatable (LAR) was assessed using Cox regression analysis, Harrell's C-index, and survival analysis. A classification and regression tree (CART) was used to determine the optimal threshold for tumor burden. RESULTS: A total of 204 patients were included. Somatostatin receptor-expressing tumor volume (SRETV) and liver SRETV derived from a relative fixed threshold of 30% (SRETV30 and liver SRETV30) were statistically significantly associated with OS (C-index: 0.802 [95% confidence interval (CI), 0.658-0.946] and 0.806 [95% CI, 0.664-0.948], respectively). Extrahepatic tumor burden was not correlated with OS (hazard ratio: 0.617, 95% CI: 0.241-1.574, P = 0.312). Among 155 patients with non-functional NETs with a ki-67 index of ≤ 10%, those with a high SRETV30 (P = 0.016) or high liver SRETV30 (P = 0.014) showed statistically significantly worse PFS on treatment with octreotide LAR. Patients receiving a higher dose of octreotide LAR normalized by SRETV30 or liver SRETV30 (a normalized dose or a liver normalized dose) showed prolonged PFS on treatment with octreotide LAR and a prolonged OS. CONCLUSION: Quantitative tumor burden based on [68 Ga]Ga-DOTA-NOC PET/CT was correlated with OS and PFS in patients with non-functional NETs with a ki-67 index of ≤ 10% who received octreotide LAR. Calculating normalized and liver normalized doses may help in selecting the starting dose of octreotide LAR.

SPECT at the speed of PET: a feasibility study of CZT-based whole-body SPECT/CT in the post 177Lu-DOTATATE and 177Lu-PSMA617 setting.

PURPOSE: To evaluate the feasibility of using the StarGuide (General Electric Healthcare, Haifa, Israel), a new generation multi-detector cadmium-zinc-telluride (CZT)-based SPECT/CT, for whole-body imaging in the setting of post-therapy imaging of 177Lu-labeled radiopharmaceuticals. METHODS: Thirty-one patients (34-89 years old; mean ± SD, 65.5 ± 12.1) who were treated with either 177Lu-DOTATATE (n=17) or 177Lu-PSMA617 (n=14) as part of standard of care were scanned post-therapy with the StarGuide; some were also scanned with the standard GE Discovery 670 Pro SPECT/CT. All patients had either 64Cu-DOTATATE or 18F-DCFPyL PET/CT prior to first cycle of therapy for eligibility check. The detection/targeting rate (lesion uptake greater than blood pool uptake) of large lesions meeting RECIST 1.1 size criteria on post-therapy StarGuide SPECT/CT was evaluated and compared to the standard design GE Discovery 670 Pro SPECT/CT (when available) and pre-therapy PET by two nuclear medicine physicians with consensus read. RESULTS: This retrospective analysis identified a total of 50 post-therapy scans performed with the new imaging protocol from November 2021 to August 2022. The StarGuide system acquired vertex to mid-thighs post-therapy SPECT/CT scans with 4 bed positions, 3 min/bed and a total scan time of 12 min. In comparison, the standard GE Discovery 670 Pro SPECT/CT system typically acquires images in 2 bed positions covering the chest, abdomen, and pelvis with a total scan time of 32 min. The pre-therapy 64Cu-DOTATATE PET takes 20 min with 4 bed positions on GE Discovery MI PET/CT, and 18F-DCFPyL PET takes 8-10 min with 4-5 bed positions on GE Discovery MI PET/CT. This preliminary evaluation showed that the post-therapy scans acquired with faster scanning time using StarGuide system had comparable detection/targeting rate compared to the Discovery 670 Pro SPECT/CT system and detected large lesions defined by RECIST criteria on the pre-therapy PET scans. CONCLUSION: Fast acquisition of whole-body post-therapy SPECT/CT is feasible with the new StarGuide system. Short scanning time improves the patients' clinical experience and compliance which may lead to increased adoption of post-therapy SPECT. This opens the possibility to offer imaged-based treatment response assessment and personalized dosimetry to patients referred for targeted radionuclide therapies.

The relationship between tumour dosimetry, response, and overall survival in patients with unresectable Neuroendocrine Neoplasms (NEN) treated with 177Lu DOTATATE (LuTate).

Peptide Receptor Radionuclide Therapy (PRRT) delivers targeted radiation to Somatostatin Receptor (SSR) expressing Neuroendocrine Neoplasms (NEN). We sought to assess the predictive and prognostic implications of tumour dosimetry with respect to response by 68 Ga DOTATATE (GaTate) PET/CT molecular imaging tumour volume of SSR (MITVSSR) change and RECIST 1.1, and overall survival (OS). METHODS: Patients with gastro-entero-pancreatic (GEP) NEN who received LuTate followed by quantitative SPECT/CT (Q-SPECT/CT) the next day (Jul 2010 to Jan 2019) were retrospectively reviewed. Single time-point (STP) lesional dosimetry was performed for each cycle using population-based pharmacokinetic modelling. MITVSSR and RECIST 1.1 were measured at 3-months post PRRT. RESULTS: Median of 4 PRRT cycles were administered to 90 patients (range 2-5 cycles; mean 27.4 GBq cumulative activity; mean 7.6 GBq per cycle). 68% received at least one cycle with radiosensitising chemotherapy (RSC). RECIST 1.1 partial response was 24%, with 70% stable and 7% progressive disease. Cycle 1 radiation dose in measurable lesions was associated with local response (odds ratio 1.5 per 50 Gy [95% CI: 1.1-2.0], p = 0.002) when adjusted by tumour grade and RSC. Median change in MITVSSR was -63% (interquartile range -84 to -29), with no correlation with radiation dose to the most avid lesion on univariable or multivariant analyses (5.6 per 10 Gy [95% CI: -1.6, 12.8], p = 0.133). OS at 5-years was 68% (95% CI: 56-78%). Neither baseline MITVSSR (hazard ratio 1.1 [95% CI: 1.0, 1.2], p = 0.128) nor change in baseline MITVSSR (hazard ratio 1.0 [95% CI: 1.0, 1.1], p = 0.223) were associated with OS when adjusted by tumour grade and RSC but RSC was (95% CI: 0.2, 0.8, p = 0.012). CONCLUSION: Radiation dose to tumour during PRRT was predictive of radiologic response but not survival. Survival outcomes may relate to other biological factors. There was no evidence that MITVSSR change was associated with OS, but a larger study is needed.

The predictive value of pretherapy [68Ga]Ga-DOTA-TATE PET and biomarkers in [177Lu]Lu-PRRT tumor dosimetry.

PURPOSE: Metastatic neuroendocrine tumors (NETs) overexpressing type 2 somatostatin receptors are the target for peptide receptor radionuclide therapy (PRRT) through the theragnostic pair of 68Ga/177Lu-DOTATATE. The main purpose of this study was to develop machine learning models to predict therapeutic tumor dose using pre therapy 68Ga -PET and clinicopathological biomarkers. METHODS: We retrospectively analyzed 90 segmented metastatic NETs from 25 patients (M14/F11, age 63.7 ± 9.5, range 38-76) treated by 177Lu-DOTATATE at our institute. Patients underwent both pretherapy [68Ga]Ga-DOTA-TATE PET/CT and four timepoints SPECT/CT at ~ 4, 24, 96, and 168 h post-177Lu-DOTATATE infusion. Tumors were segmented by a radiologist on baseline CT or MRI and transferred to co-registered PET/CT and SPECT/CT, and normal organs were segmented by deep learning-based method on CT of the PET and SPECT. The SUV metrics and tumor-to-normal tissue SUV ratios (SUV_TNRs) were calculated from 68Ga -PET at the contour-level. Posttherapy dosimetry was performed based on the co-registration of SPECT/CTs to generate time-integrated-activity, followed by an in-house Monte Carlo-based absorbed dose estimation. The correlation between delivered 177Lu Tumor absorbed dose and PET-derived metrics along with baseline clinicopathological biomarkers (such as Creatinine, Chromogranin A and prior therapies) were evaluated. Multiple interpretable machine-learning algorithms were developed to predict tumor dose using these pretherapy information. Model performance on a nested tenfold cross-validation was evaluated in terms of coefficient of determination (R2), mean-absolute-error (MAE), and mean-relative-absolute-error (MRAE). RESULTS: SUVmean showed a significant correlation (q-value < 0.05) with absorbed dose (Spearman ρ = 0.64), followed by TLSUVmean (SUVmean of total-lesion-burden) and SUVpeak (ρ = 0.45 and 0.41, respectively). The predictive value of PET-SUVmean in estimation of posttherapy absorbed dose was stronger compared to PET-SUVpeak, and SUV_TNRs in terms of univariate analysis (R2 = 0.28 vs. R2 ≤ 0.12). An optimal trivariate random forest model composed of SUVmean, TLSUVmean, and total liver SUVmean (normal and tumoral liver) provided the best performance in tumor dose prediction with R2 = 0.64, MAE = 0.73 Gy/GBq, and MRAE = 0.2. CONCLUSION: Our preliminary results demonstrate the feasibility of using baseline PET images for prediction of absorbed dose prior to 177Lu-PRRT. Machine learning models combining multiple PET-based metrics performed better than using a single SUV value and using other investigated clinicopathological biomarkers. Developing such quantitative models forms the groundwork for the role of 68Ga -PET not only for the implementation of personalized treatment planning but also for patient stratification in the era of precision medicine.

Efficacy and safety of peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE in 15 patients with progressive treatment-refractory meningioma.

PURPOSE: There is no evidence-based systemic therapy for patients with progressive meningiomas for whom surgery or external radiotherapy is no longer an option. In this study, the efficacy and safety of peptide receptor radionuclide therapy (PRRT) in patients with progressive, treatment-refractory meningiomas were evaluated. METHODS: Retrospective analysis of all meningioma patients treated with [177Lu]Lu-DOTA-TATE from 2000 to 2020 in our centre. Primary outcomes were response according to RANO bidimensional and volumetric criteria and progression-free survival (PFS). Overall survival (OS) and tumour growth rate (TGR) were secondary endpoints. TGR was calculated as the percentage change in surface or volume per month. RESULTS: Fifteen meningioma patients received [177Lu]Lu-DOTA-TATE (7.5-29.6 GBq). Prior to PRRT, all patients had received external radiotherapy, and 14 patients had undergone surgery. All WHO grades were included WHO 1 (n=3), WHO 2 (n=5), and WHO 3 (n=6). After PRRT, stable disease was observed in six (40%) patients. The median PFS was 7.8 months with a 6-month PFS rate of 60%. The median OS was 13.6 months with a 12-month OS rate of 60%. All patients had progressive disease prior to PRRT, with an average TGR of 4.6% increase in surface and 14.8% increase in volume per month. After PRRT, TGR declined to 3.1% in surface (p=0.016) and 5.0% in volume (p=0.013) per month. CONCLUSION: In this cohort of meningioma patients with exhaustion of surgical and radiotherapeutic options and progressive disease, it was shown that PRRT plays a role in controlling tumour growth.

Semi-automated segmentation methods of SSTR PET for dosimetry prediction in refractory meningioma patients treated by SSTR-targeted peptide receptor radionuclide therapy.

OBJECTIVES: Tumor dosimetry with somatostatin receptor-targeted peptide receptor radionuclide therapy (SSTR-targeted PRRT) by 177Lu-DOTATATE may contribute to improved treatment monitoring of refractory meningioma. Accurate dosimetry requires reliable and reproducible pretherapeutic PET tumor segmentation which is not currently available. This study aims to propose semi-automated segmentation methods to determine metabolic tumor volume with pretherapeutic 68Ga-DOTATOC PET and evaluate SUVmean-derived values as predictive factors for tumor-absorbed dose. METHODS: Thirty-nine meningioma lesions from twenty patients were analyzed. The ground truth PET and SPECT volumes (VolGT-PET and VolGT-SPECT) were computed from manual segmentations by five experienced nuclear physicians. SUV-related indexes were extracted from VolGT-PET and the semi-automated PET volumes providing the best Dice index with VolGT-PET (Volopt) across several methods: SUV absolute-value (2.3)-threshold, adaptative methods (Jentzen, Otsu, Contrast-based method), advanced gradient-based technique, and multiple relative thresholds (% of tumor SUVmax, hypophysis SUVmean, and meninges SUVpeak) with optimal threshold optimized. Tumor-absorbed doses were obtained from the VolGT-SPECT, corrected for partial volume effect, performed on a 360° whole-body CZT-camera at 24, 96, and 168 h after administration of 177Lu-DOTATATE. RESULTS: Volopt was obtained from 1.7-fold meninges SUVpeak (Dice index 0.85 ± 0.07). SUVmean and total lesion uptake (SUVmeanxlesion volume) showed better correlations with tumor-absorbed doses than SUVmax when determined with the VolGT (respective Pearson correlation coefficients of 0.78, 0.67, and 0.56) or Volopt (0.64, 0.66, and 0.56). CONCLUSION: Accurate definition of pretherapeutic PET volumes is justified since SUVmean-derived values provide the best tumor-absorbed dose predictions in refractory meningioma patients treated by 177Lu-DOTATATE. This study provides a semi-automated segmentation method of pretherapeutic 68Ga-DOTATOC PET volumes to achieve good reproducibility between physicians. CLINICAL RELEVANCE STATEMENT: SUVmean-derived values from pretherapeutic 68Ga-DOTATOC PET are predictive of tumor-absorbed doses in refractory meningiomas treated by 177Lu-DOTATATE, justifying to accurately define pretherapeutic PET volumes. This study provides a semi-automated segmentation of 68Ga-DOTATOC PET images easily applicable in routine. KEY POINTS: • SUVmean-derived values from pretherapeutic 68Ga-DOTATOC PET images provide the best predictive factors of tumor-absorbed doses related to 177Lu-DOTATATE PRRT in refractory meningioma. • A 1.7-fold meninges SUVpeak segmentation method used to determine metabolic tumor volume on pretherapeutic 68Ga-DOTATOC PET images of refractory meningioma treated by 177Lu-DOTATATE is as efficient as the currently routine manual segmentation method and limits inter- and intra-observer variabilities. • This semi-automated method for segmentation of refractory meningioma is easily applicable to routine practice and transferrable across PET centers.

68Ga-DOTA-peptide PET/CT for radiotherapy planning and evaluating treatment response in the management of meningiomas.

Meningiomas overexpress somatostatin receptors (SSTR). PET imaging with SSTR ligands such as 68Ga-DOTA-peptide has recently shown high diagnostic accuracy in identification of meningiomas due to lack of normal bone and brain activity. PET-derived parameters, especially gross tumour volume (GTV) delineation improves inter-observer variability and appears to be particularly promising for RT planning. The potential strength of 68Ga-DOTA in the ongoing assessment of treatment response and disease progression in meningioma, particularly in the post-surgical and post-radiation settings is encouraging. More prospective randomized studies with large cohorts of patients are required to define the effective role of this modality.

Radiopharmaceuticals used for diagnosis and therapy of NETs.

The first description of the in vivo visualization of somatostatin receptor-positive tumors in patients was based on the use of a radioiodine (123I) labelled somatostatin analogue (Krenning et al. 1989). In the years that followed an Indium-111 (111In) labelled somatostatin analogue, chelated with diethylenetriaminepentaacetic acid (DTPA), was successfully developed. Subsequently, 111In-OctreoScan was introduced worldwide. In the years to come 99mTc-Tektrotyde became commercially available with easy access. In the last decade, with the increasing use of positron emission tomography (PET) imaging, somatostatin analogues have been labelled with various positron-emitting isotopes, such as Gallium-68 (68Ga) and Copper-64 (64Cu) (Lewis et al. 1999, Schottelius et al. 2004, Gabriel et al. 2007) e.g 68Ga-DOTATOC, 68Ga-DOTATATE 68Ga-DOTANOC and 68Cu-DOTATATE. Scintigraphy with these investigational compounds display encouraging good imaging quality amd improved sensitivity in tumor site detection compared with SPECT scintigraphy. Also, other PET radiopharmaceuticals were developed, such as 18F-dihydroxy-phenyl-alanine (18F-DOPA) and 11C-labelled 5-hydroxytryptophan (11C-5-HTP) with encouraging results in terms of visualization of GEP-NETs (Koopmans et al. 2008). After the successful introduction of SRS in the diagnosis and staging of NETs, the next logical step was to increase the administered activity so that the radiopharmaceutical can induce tumor shrinkage in patients who had inoperable and/or metastasized NENs. Therefore, the first peptide receptor radionuclide therapy (PRRT) was performed with high administered activity of [111In-DTPA0] octreotide (Krenning et al. 1994a). To make significant advancements in the treatment of somatostatin receptor-positive metastatic disease, more efficient radiolabelled somatostatin analogues were developed with higher affinity to the somatostatin receptor. Treatment with radiolabelled peptides or PRRT is a promising new therapeutic option in the management of inoperable or metastasized NETs. Symptomatic control can be achieved with all 111In-, 90Y- and 177Lu-labelled somatostatin analogue-based PRRT. For objective response and long-lasting duration of response, 90Y-DOTATOC and 177Lu-DOTATATE are the most promising radiopharmaceuticals. Side effects of PRRT are few and mild, if adequate kidney protective measures are taken and dose-limits are respected. In a minority of patients, when SRS fails to identify neuroendocrine disease, MIBG scintigraphy and subsequent 131I-MBG therapy might be an alternative treatment option. Targeted alpha-particle therapy (TAT) has emerged as an alternative treatment option to beta emitters in PRRT. The use of alpha emitters for cancer therapy has two advantages over beta emitter PRRT. The short range of alpha particles of only a few cell diameters (<0.1mm) allows for selective ablation of the target cancer cells, while sparing the surrounding healthy tissue. In addition, the higher linear energy transfer (LET), when compared to conventional beta emitters, results in the formation of complex DNA double-strand and DNA cluster breaks, which ultimately lead to cell death.(Lassmann M et al. Ann ICRP. 2018) Putative radiopharmaceuticals that can be considered for metastatic NEN treatment include Actinium-225 (225Ac)-DOTATATE and Bismuth-213 (213Bi)-DOTATOC. There was evidence of partial response using both radiopharmaceutical agents without significant hematological, renal, or hepatotoxicity. Future studies should consider longer term, randomized controlled trials investigating the role of TAT, in particular, 225c-DOTATATE, in the treatment of metastatic NENs. Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumors (NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localization of the primary and metastatic disease remains the ultimate goal of research.

Efficacy and safety of 177Lu­DOTATATE in patients with advanced pancreatic neuroendocrine tumours: data from the NETTER-R international, retrospective study.

PURPOSE: NETTER-R aimed to determine the efficacy, safety and tolerability of 177Lu-DOTATATE in patients with progressive, advanced pancreatic neuroendocrine tumours (panNETs) using retrospective real-world data from multiple sites. METHODS: This international study retrospectively included patients with panNETs treated with 177Lu-DOTATATE. The primary endpoint was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included overall survival (OS), safety and tumour response. RESULTS: In total, 110 patients with panNETs were studied; 65.5% received a cumulative dose of 177Lu-DOTATATE 29.6 GBq ± 10% (median: 7.4 GBq). In 62 patients with available RECIST v1.1 tumour response, the median PFS was 24.8 months (95% confidence interval [CI]: 17.5-34.5), and the objective response rate was 40.3% (95% CI: 28.1-53.6); all responses were partial. With a median follow up of 24.5 months (range: 2.0-123.4 months) after the first cycle of 177Lu-DOTATATE, the median OS in the full analysis set (n = 110) was 41.4 months (95% CI: 28.6-50.2). PFS (hazard ratio [HR]: 3.672; p = 0.0009) and OS (HR: 3.360; p < 0.0001) were longer in patients who received no chemotherapy prior to 177Lu-DOTATATE than those who did. No treatment-emergent adverse events (TEAEs) led to treatment discontinuation. Grade 3 anaemia, lymphopenia and thrombocytopenia occurred in 0.9%, 5.4% and 0.9% of patients, respectively. No acute leukaemia or myelodysplastic syndrome was reported. Six patients (5.5%) had renal TEAEs. All renal grade ≥ 3 events were transient and did not lead to treatment modification. CONCLUSIONS: These results reinforce the role of 177Lu-DOTATATE for the treatment of patients with advanced, somatostatin receptor-positive panNETs.

Induction therapy with 177Lu-DOTATATE procures long-term survival in locally advanced or oligometastatic pancreatic neuroendocrine neoplasm patients.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE induces objective response in up to 57% of pancreatic neuroendocrine neoplasms (panNENs). Therefore, PRRT may comprise a downstaging option for panNEN patients who are not eligible for upfront curative surgery or are at high risk for recurrence. The aim of this study was to assess the potency of induction PRRT for locally advanced panNENs and to evaluate the effect of surgery after PRRT on overall survival (OS). METHODS: Retrospective cohort study of panNEN patients treated with induction 177Lu-DOTATATE. RESULTS: After PRRT, 26 out of 49 patients underwent pancreatic surgery with curative intent (PRRT + surgery). Partial objective response was obtained in 62% of the PRRT + surgery group versus 26% of the patients not undergoing panNEN surgery (PRRT-only group, p = 0.02). Downstaging in tumour-vessel interface was observed in 38% of all patients with at least one involved vessel. Median OS was 14.7 years (95% CI 5.9-23.6) for the PRRT + surgery group compared to 5.5 years (95% CI 4.5-6.5) for the PRRT-only group (p = 0.003). In the Cox proportional hazards analysis, surgery was not significantly associated with OS after propensity score adjustment with cumulative activity, performance status, tumour size after PRRT, and tumour grade. Median progression-free survival was 5.3 years (95% CI 2.4-8.1) for the PRRT + surgery group and 3.0 years (95% CI 1.6-4.4) for the PRRT-only group (p = 0.02). CONCLUSION: Early administration of PRRT followed by surgery is associated with favourable long-term outcomes in patients with locally advanced or oligometastatic panNEN and can be considered for selected patients with vascular involvement and/or increased risk of recurrence.