Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1–2 (G1–G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21–54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3–4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

⁶⁴Cu-DOTATATE PET/CT imaging 1 hour (h) post-injection (p.i.) is excellent for lesion detection in patients with neuroendocrine neoplasms (NEN). We hypothesized that the imaging time window can be extended up to 3h p.i. without significant differences in the number of lesions detected. Methods From a prospective study, we compared, on a head-to-head basis, sets of ⁶⁴Cu-DOTATATE PET/CT images from 35 patients with NEN scanned 1h and 3h p.i. of 200 MBq ⁶⁴Cu-DOTATATE. The number of lesions on both scans were counted and grouped according to organs or regions and compared with negative binomial regression. Discordant lesions (visible on the 1h or 3h p.i. ⁶⁴Cu-DOTATATE PET but not the other) were considered true if found on simultaneous CT or later MR, CT or somatostatin receptor imaging. We measured lesion maximal standardized uptake values (SUV_max), reference normal organ or tissue mean SUV (SUV_mean) and tumor-to-normal tissue ratios (TTN) calculated from SUV_max/ SUV_mean. Results We found 822 concordant lesions (visible on both the 1h and 3h p.i. ⁶⁴Cu-DOTATATE PET) and five discordant lesions of which four were considered true. One discordant case in one patient involved a discordant organ system (lymph node) detected on the 3h p.i. but not the 1h p.i. ⁶⁴Cu-DOTATATE PET that did not alter the patient’s disease stage (stage IV) because the patient had 11 additional concordant liver lesions. We found no significant differences between the number of lesions detected on the 1h and 3h p.i. ⁶⁴Cu-DOTATATE PET. Throughout the 1-3 h p.i. imaging window, TTN (mean [95% confidence interval]) remained high in all key organs: Liver (1h p.i.: 12.6 [10.2; 14.9] , 3h p.i.: 11.0 [8.7; 13.4]), intestines (1h p.i.: 24.2 [14.9; 33.4], 3h p.i.: 28.2 [16.5; 40.0]), pancreas (1h p.i.: 42.4 [12.3; 72.5], 3h p.i.: 41.1 [8.7; 73.4]) and bone (1h p.i.: 103.0 [38.6; 167.4], 3h p.i.: 124.2 [57.1; 191.2]). Conclusion The imaging time window of ⁶⁴Cu-DOTATATE PET/CT of patients with NEN can be expanded from 1h p.i. to 1-3 hours p.i. without significant differences in the number of lesions detected.

Overexpression of somatostatin receptors (SSTRs) in patients with neuroendocrine neoplasms (NENs) is used for both diagnosis and treatment. Receptor density may reflect tumor differentiation and thus be associated with prognosis. Noninvasive visualization and quantification of SSTR density is possible by SSTR imaging (SRI) using PET. Recently, we introduced ⁶⁴Cu-DOTATATE for SRI, and we hypothesized that uptake of this tracer could be associated with overall survival (OS) and progression-free survival (PFS). Methods: We evaluated patients with NENs who underwent ⁶⁴Cu-DOTATATE PET/CT SRI in 2 prospective studies. Tracer uptake was determined as the maximal SUV (SUV_max) for each patient. Kaplan–Meier analysis with log-rank was used to determine the predictive value of ⁶⁴Cu-DOTATATE SUV_max for OS and PFS. Specificity, sensitivity, and accuracy were calculated for prediction of outcome at 24 mo after ⁶⁴Cu-DOTATATE PET/CT. Results: In total, 128 patients with NENs were included and followed for a median of 73 mo (range, 1–112 mo). During follow-up, 112 experienced disease progression, and 69 died. The optimal cutoff for ⁶⁴Cu-DOTATATE SUV_max was 43.3 for prediction of PFS, with a hazard ratio of 0.56 (95% confidence interval, 0.38–0.84) for patients with an SUV_max of more than 43.3. However, no significant cutoff was found for prediction of OS. In multiple Cox regression adjusted for age, sex, primary tumor site, and tumor grade, the SUV_max cutoff hazard ratio was 0.50 (range, 0.32–0.77) for PFS. The accuracy was moderate for predicting PFS (57%) at 24 mo after ⁶⁴Cu-DOTATATE PET/CT. Conclusion: In this first study to report the association of ⁶⁴Cu-DOTATATE PET/CT and outcome in patients with NENs, tumor SSTR density as visualized with ⁶⁴Cu-DOTATATE PET/CT was prognostic for PFS but not OS. However, the accuracy of prediction of PFS at 24 mo after ⁶⁴Cu-DOTATATE PET/CT SRI was moderate, limiting the value on an individual-patient basis.

The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Non-invasive tools to improve prognostication and guide decisions on treatment are warranted. Expression of urokinase plasminogen activator receptor (uPAR) is present in many cancer types and associated with a poor outcome. Therefore, using an in-house developed uPAR PET tracer (⁶⁸Ga-NOTA-AE105) we aimed to assess uPAR expression in NENs. We hypothesized that uPAR expression was detectable in a significant proportion of patients and associated with a poorer outcome. In addition, as uPAR-targeted radionuclide therapy has previously proven effective in preclinical models, the study would also indicate the potential for uPAR-targeted radionuclide therapy in NEN patients. METHODS: In a prospective clinical phase II trial, we included 120 patients with NENs of all grades of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was acquired 20 minutes after injection of approximately 200 MBq ⁶⁸Ga-NOTA-AE105. uPAR target-to-liver ratio (uPAR TLR) was used to define lesions as uPAR positive when lesion SUV_max /liver SUVmean ≥ 2. Patients were followed for at least 1 year to assess progression-free survival (PFS) and overall survival (OS). RESULTS: The majority of patients had small intestinal NEN (n = 61) and metastatic disease (n = 86). uPAR positive lesions were seen in 68% (n = 65) of all patients and in 75% (n = 18) of patients with high grade disease (NEN G3). During follow-up (median 28 months), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as uPAR TLR above median, had a hazard ratio (95% confidence interval) of 1.87 (1.11-3.17) and 2.64 (1.19-5.88) for PFS and OS, respectively (p<0.05 for both). CONCLUSION: Using ⁶⁸Ga-NOTA-AE105 PET for imaging uPAR in patients with NEN, uPAR positive lesions were seen in the majority of patients and most notably in patients with both low and high grade NEN. Furthermore, uPAR expression was associated with a worse prognosis. We suggest that uPAR PET is relevant for risk stratification and uPAR may be a promising target for therapy in patients with NEN.

Background: Segmentation of neuroendocrine neoplasms (NENs) in [⁶⁴Cu]Cu-DOTATATE positron emission tomography makes it possible to extract quantitative measures useable for prognostication of patients. However, manual tumor segmentation is cumbersome and time-consuming. Therefore, we aimed to implement and test an artificial intelligence (AI) network for tumor segmentation. Patients with gastroenteropancreatic or lung NEN with [⁶⁴Cu]Cu-DOTATATE PET/CT performed were included in our training (n = 117) and test cohort (n = 41). Further, 10 patients with no signs of NEN were included as negative controls. Ground truth segmentations were obtained by a standardized semiautomatic method for tumor segmentation by a physician. The nnU-Net framework was used to set up a deep learning U-net architecture. Dice score, sensitivity and precision were used for selection of the final model. AI segmentations were implemented in a clinical imaging viewer where a physician evaluated performance and performed manual adjustments. Results: Cross-validation training was used to generate models and an ensemble model. The ensemble model performed best overall with a lesion-wise dice of 0.850 and pixel-wise dice, precision and sensitivity of 0.801, 0.786 and 0.872, respectively. Performance of the ensemble model was acceptable with some degree of manual adjustment in 35/41 (85%) patients. Final tumor segmentation could be obtained from the AI model with manual adjustments in 5 min versus 17 min for ground truth method, p < 0.01. Conclusion: We implemented and validated an AI model that achieved a high similarity with ground truth segmentation and resulted in faster tumor segmentation. With AI, total tumor segmentation may become feasible in the clinical routine.

Patients with neuroendocrine neoplasms (NEN) have heterogeneous somatostatin receptor expression with highly differentiated lesions having higher expression. Receptor expression of the total tumor burden may be visualized by somatostatin receptor imaging, e.g. ⁶⁴Cu-DOTATATE PET/CT. Assessment of maximal lesion uptake is associated with progression-free survival (PFS), but not overall survival (OS). We hypothesized that the lesion with lowest, rather than highest, ⁶⁴Cu-DOTATATE uptake would be more prognostic and developed a semi-automatic method for evaluating this. Methods: Patients with NEN underwent ⁶⁴Cu-DOTATATE PET/CT. A standardized semi-automatic tumor delineation method was developed and used to identify the lesion with the lowest uptake, i.e. lowest of lesion mean standardized uptake values (SUV)mean. Additionally, we assessed total tumor volume derived from the semi-automatic tumor delineation. Kaplan-Meier and Cox regression analyses were used to determine association with OS and PFS. Results: In 116 patients with NEN, median PFS (95% confidence interval) was 23 (20-31) months and median OS was 85 (68-113) months. Minimum SUVmean and total tumor volume were significantly associated with PFS and OS in univariate Cox regression analyses, while SUV_max was only significant for PFS. In multivariate Cox analyses, both minimum SUVmean and total tumor volume remained statistically significant. Minimum SUVmean and total tumor volume were then dichotomized by their median, and patients were categorized into 4 groups: High/low total tumor volume and high/low minimum SUVmean. Patients with low total tumor volume and high minimum SUVmean had a hazard ratio (95% confidence interval) of 0.32 (0.20-0.51) for PFS and 0.24 (0.13-0.43) for OS, both P<0.001 (reference: high total tumor volume and low minimum SUVmean). Conclusion: We propose a standardized semi-automatic tumor delineation method to identify the lesion with lowest ⁶⁴Cu-DOTATATE uptake and total tumor volume. Assessment of lowest, rather than highest lesion uptake greatly increases prognostication by ⁶⁴Cu-DOTATATE PET/CT. Combing lesion uptake and total tumor volume, we derived a novel prognostic classification of patients with NEN.