Peptide receptor radionuclide therapy (PRRT) in metastatic neuroendocrine tumors of unknown primary (CUP-NETs).

Rationale: Peptide receptor radionuclide therapy (PRRT) for the treatment of neuroendocrine tumors (NETs) has been explored for more than two decades, but there are only limited data on the treatment of NETs of unknown primary site (CUP-NETs). This study aimed to analyze the long-term outcome, efficacy, and safety of PRRT in patients with CUP-NETs. Methods: Patients with pathologically confirmed metastatic CUP-NET who received lutetium-177 (177Lu) and/or yttrium-90 (90Y) labeled somatostatin analogs between March 2001 and March 2019 were retrospectively reviewed; those patients were referred as cCUP-NETs (clinical CUP-NETs). Eighty-one patients had unknown primary tumors even after [68Ga]Ga-SSTR and [18F]FDG PET/CT and were classified as pCUP-NETs (PET CUP-NETs). Treatment response was assessed according to RECIST 1.1 and PERCIST. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier analysis, and adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Results: A total of 575 PRRT cycles were administered to 156 patients (76 men and 80 women) evaluable for analysis: these patients were monitored for a median period of 92.3 mo (range, 4.0-169.1 mo). The disease control rate was 41.4% (43.4%) by RECIST and 40.2% (40.8%) by PERCIST in cCUP-NENs (pCUP-NETs). The objective response rate (ORR) with PRRT was 29.4% and 32.2% in cCUP-NENs and pCUP-NETs, respectively. The median PFS and OS for the entire cohort were 17.4 mo (95% confidence interval [95% CI], 11.4-23.4) and 67.4 mo (95% CI, 47.2-87.2) for all patients, respectively. The median OS for G3 tumors was significantly lower (15 mo) than for patients with G1 NET (85.5 mo), G2 (71.7 mo), and for patients with unknown grade (63.3 mo) NETs (P = 0.186, HR: 10.6, 95% CI: 3.87, 28.97, P = 0.09). PRRT was well tolerated by all patients. During treatment and long-term follow-up, CTCAE grade 3 and grade 4 thrombocytopenia and leukocytopenia were observed in only 3 patients (1.9%); there was no evidence of renal or hepatic toxicity. Conclusion: In a large cohort of patients with advanced CUP-NETs treated with PRRT in a real-world scenario and followed up to 14 years after the commencement, PRRT has demonstrated favorable and clinically significant efficacy and survival with minimal and acceptable side effects. Our results indicate that PRRT is a well-tolerated and effective treatment option for patients with metastatic CUP-NETs expressing somatostatin receptors.

Long-term Nephrotoxicity after PRRT: Myth or Reality.

Rationale: The kidneys are commonly considered as the potential dose-limiting organ for peptide receptor radionuclide therapy (PRRT), making the risk of nephrotoxicity a primary concern. This retrospective analysis with prospective documentation and long-term follow-up aims to assess the risk of nephrotoxicity after PRRT in a large cohort of patients with neuroendocrine neoplasms (NENs) treated at our institution over the past 18 years. Methods: A total of 1361 NEN patients treated with 1-10 cycles of 177Lu-DOTA-TOC/-NOC/-TATE, 90Y-DOTA-TOC/-NOC/-TATE, DUO-PRRT (sequential administration of 90Y- and 177Lu-), or TANDEM-PRRT (combination of 90Y- and 177Lu- on the same day concomitantly) were included in this analysis. All parameters were prospectively documented in a structured database comprising over 250 items per patient and retrospectively analyzed. Kidney function, including serum creatinine, blood urea nitrogen, cGFR, and electrolytes, was evaluated before each PRRT cycle and during follow-up. Restaging was regularly performed at 6-month intervals until death. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0). Results: Between 2000 and 2018, a total of 5409 cycles of PRRT were administered to 1361 NEN patients. Follow-up after complete treatment was available for 1281 patients receiving 4709 cycles of PRRT, with a median follow-up time of 69.2 months (interquartile range, 32.8-110.5 months) and a maximum follow-up time of 175 months. Baseline creatinine levels were normal in 1039/1281 (81.1%) subjects, while grade 1 (G1) renal insufficiency was present in 221/1281 (17.3%) prior to PRRT. G2 was present in 19/1281 (1.5%), and G3 in 2/1281 (0.2%). After treatment, the proportion of G3/G4 grade patients only increased from 0.2% to 0.7%. Mean creatinine levels increased from a baseline of 0.90 ± 0.30 to 1.01 ± 0.57 mg/L (80.0 ± 26.7 to 89.4 ± 50.8 µmol/L) after treatment. In our main analysis cohort of 1244 patients (4576 cycles), 200 patients experienced an increase in CTCAE creatinine grade. Age, number of treatment cycles, type of radionuclides, and length of follow-up time were the main factors affecting CTCAE creatinine grading after treatment. When comparing the subgroups treated with different radionuclides, the risk of nephrotoxicity after 90Y treatment alone and the 90Y/177Lu combination group was higher than after 177Lu treatment alone. In the 90Y treatment subgroup, the two significant risk factors for an increased CTCAE creatinine grade were identified to be age (≥60) and a long follow-up time. Conclusions: This retrospective analysis with prospective documentation in a large cohort of 1281 NEN patients receiving 4709 cycles of PRRT co-administered with renal protection, treated through the individualized approach at a single institution over 18 years, did not reveal any evidence of long-term PRRT-related renal toxicity. The results of our study suggest that with the use of proper renal protection, nephrotoxicity due to PRRT is more likely a myth than a reality.

Extended peptide receptor radionuclide therapy: evaluating nephrotoxicity and therapeutic effectiveness in neuroendocrine tumor patients receiving more than four treatment cycles.

PURPOSE: Currently, the most used peptide receptor radionuclide therapy (PRRT) regimen for neuroendocrine tumors comprises 4 treatment cycles, and there is not enough large-scale data to support the safety of more individualized extended PRRT. This study aims to evaluate the therapeutic effectiveness and potential nephrotoxicity related to PRRT using more than four treatment cycles. METHODS: In this retrospective analysis, we included patients who had received at least four PRRT cycles and had available follow-up data. We analyzed renal function indicators before and after multiple treatments, comparing nephrotoxicity in patients receiving four cycles ("standard") with those receiving more than four ("extended treatment"). Nephrotoxicity was assessed via creatinine levels and CTCAE creatinine grades. Treatment effectiveness was gauged using Kaplan-Meier survival analysis, focusing on overall survival and disease-specific survival (DSS). Statistical analyses were performed using SPSS version 26 (IBM), R 4.2.3, and GraphPad Prism 9.0.0. Statistical significance was defined as a P-value of less than 0.05. RESULTS: Our study cohort consisted of 281 patients in the standard group and 356 in the extended treatment group. No significant differences in baseline characteristics or renal function were noted between the two groups pre-treatment. Mean post-treatment creatinine levels did not significantly differ between the standard (89.30 ± 51.19 µmol/L) and extended treatment groups (93.20 ± 55.98 µmol/L; P = 0.364). Similarly, there was no statistical significance between the CTCAE creatinine grades of the two groups (P = 0.448). Adverse renal events were observed in 0.4% of patients in the standard group and 1.1% in the extended treatment group. After a median follow-up time of 88.3 months, we found that median overall survival was significantly higher in the extended treatment group (72.8 months) compared to the standard treatment group (52.8 months). A Cox regression analysis further supported these findings, indicating a better prognosis for the extended treatment group in terms of overall survival (HR: 0.580, P < 0.001) and DSS (HR: 0.599, P < 0.001). CONCLUSION: Our findings suggest that extending PRRT treatment beyond the standard four cycles may be a safe and effective therapeutic strategy for NET patients. This approach could be particularly beneficial for patients experiencing disease recurrence or progression following standard treatment.

Rapid Tumor Washout of 177 Lu-PSMA Radioligand in Renal Cell Carcinoma.

ABSTRACT: The role of prostate-specific membrane antigen (PSMA) targeted molecular imaging and radionuclide therapy in prostate cancer is well known. PSMA is also overexpressed in the neovasculature of a number of solid tumors, including renal cell carcinoma (RCC). Several studies have demonstrated the diagnostic utility of PSMA PET imaging in the setting of RCC. To date, no PSMA radioligand therapy of RCC patient has been reported according to literature. Here, we report our experience treating a patient with metastatic RCC with 177 Lu-PSMA I&T radioligand therapy, but unexpected imaging findings with rapid washout of 177 Lu-PSMA from the tumor.

Peptide Receptor Radionuclide Therapy in Patients With Advanced Progressive Medullary Thyroid Cancer: Efficacy, Safety, and Survival Predictors.

PURPOSE: Progressive metastatic medullary thyroid carcinoma (MTC) is often characterized by rapid disease progression and poor prognosis, with only few therapeutic options available. Peptide receptor radionuclide therapy (PRRT) has demonstrated remarkable success in the management of gastroenteropancreatic neuroendocrine tumors and has also been suggested to treat MTC. However, evidence on its effectiveness and long-term outcome for this indication is still limited. The objective of this study was to assess the safety and efficacy of PRRT in patients with advanced, progressive MTC and to determine survival. Potential predictors of survival were also evaluated. METHODS: From September 2003 to June 2019, 28 patients (15 men and 13 women; mean age, 49 ± 14 years) with progressive, somatostatin receptor-positive advanced MTC received PRRT with 177Lu- or 90Y-labeled somatostatin analogs at Zentralklinik Bad Berka, Germany. Toxicity was graded according to Common Terminology Criteria for Adverse Events version 5.0. Treatment response was evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1, as well as molecular imaging criteria (European Organisation for Research and Treatment of Cancer). Kaplan-Meier analysis was used to calculate progression-free survival (PFS) and overall survival (OS), defined from the start of PRRT. Univariate and multivariate Cox regression analyses were performed to identify parameters associated with PFS and OS. RESULTS: Seventy-seven cycles of PRRT were administered (mean cumulative administered activity, 16.0 ± 7.8 GBq). No acute or long-term grade 3/4 toxicity was recorded with a follow-up of 3 to 140 months, except for 1 patient (4%) who suffered from grade 3 anemia (possibly related to disease progression). According to the RECIST criteria, the disease control rate after 3 to 4 months of PRRT was 56% (partial remission, 12%; stable disease, 44%). The disease control rate (72%) was higher by molecular response evaluation. Median OS and PFS were 63.7 and 10.1 months, respectively. The annual OS rates were 84% at 1 year, 65% at 3 years, 57% at 5 years, and 18% at 10 years. The annual PFS rates were 42% at 1 year, 21% at 2 years, and 13% at 5 years. Patients with bone metastases had poorer OS and PFS than those without metastases (median OS, 58.7 vs 92.3 months [P = 0.035; hazard ratio, 2.7; 95% confidence interval, 0.92-7.84]; median PFS, 8.5 vs 12.8 months [P = 0.592; hazard ratio, 1.2; 95% confidence interval, 0.56-2.76]). CONCLUSIONS: Peptide receptor radionuclide therapy was well tolerated and effective in patients with advanced, aggressive MTC. Bone metastasis was an independent adverse prognostic factor for OS.

Salivary Gland Toxicity of PSMA-Targeted Radioligand Therapy with 177Lu-PSMA and Combined 225Ac- and 177Lu-Labeled PSMA Ligands (TANDEM-PRLT) in Advanced Prostate Cancer: A Single-Center Systematic Investigation.

Purpose: PSMA-targeted radioligand therapy (PRLT) is a promising treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, a high uptake of the radiopharmaceutical in the salivary glands (SG) can lead to xerostomia and becomes dose-limiting for 225Ac-PSMA-617. This study investigated the sialotoxicity of 177Lu-PSMA-I&T/-617 monotherapy and co-administered 225Ac-PSMA-617 and 177Lu-PSMA-617 (Tandem-PPRLT). Methods: Three patient cohorts, that had undergone 177Lu-PSMA-I&T/-617 monotherapy or Tandem-PRLT, were retrospectively analyzed. In a short-term cohort (91 patients), a xerostomia assessment (CTCAE v.5.0), a standardized questionnaire (sXI), salivary gland scintigraphy (SGS), and SG SUVmax and the metabolic volume (MV) on 68Ga-PSMA-11-PET/CT were obtained before and after two cycles of 177Lu-PSMA-I&T/-617. In a long-term cohort, 40 patients were similarly examined. In a Tandem cohort, the same protocol was applied to 18 patients after one cycle of Tandem-PRLT. Results: Grade 1 xerostomia in the short-term follow-up was observed in 22 (24.2%) patients with a worsening of sXI from 7 to 8 at (p < 0.05). In the long-term cohort, xerostomia grades 1 to 2 occurred in 16 (40%) patients. SGS showed no significant changes, but there was a decline of the MV of all SGs. After Tandem-PRLT, 12/18 (66.7%) patients reported xerostomia grades 1 to 2, and the sXI significantly worsened from 9.5 to 14.0 (p = 0.005), with a significant reduction in the excretion fraction (EF) and MV of all SGs. Conclusion: 177Lu-PSMA-I&T/-617 causes only minor SG toxicity, while one cycle of Tandem-PRLT results in a significant SG impairment. This standardized protocol may help to objectify and quantify SG dysfunction.

Feasibility, Biodistribution, and Preliminary Dosimetry in Peptide-Targeted Radionuclide Therapy of Diverse Adenocarcinomas Using 177Lu-FAP-2286: First-in-Humans Results.

Fibroblast activation protein (FAP) is a promising target for diagnosis and therapy of numerous malignant tumors. FAP-2286 is the conjugate of a FAP-binding peptide, which can be labeled with radionuclides for theranostic applications. We present the first-in-humans results using 177Lu-FAP-2286 for peptide-targeted radionuclide therapy (PTRT). Methods: PTRT using 177Lu-FAP-2286 was performed on 11 patients with advanced adenocarcinomas of the pancreas, breast, rectum, or ovary after prior confirmation of uptake on 68Ga-FAP-2286 or 68Ga-FAPI-04 PET/CT. Results: Administration of 177Lu-FAP-2286 (5.8 ± 2.0 GBq; range, 2.4-9.9 GBq) was well tolerated, with no adverse symptoms or clinically detectable pharmacologic effects being noticed or reported in any of the patients. The whole-body effective dose was 0.07 ± 0.02 Gy/GBq (range, 0.04-0.1 Gy/GBq). The mean absorbed doses for kidneys and red marrow were 1.0 ± 0.6 Gy/GBq (range, 0.4-2.0 Gy/GBq) and 0.05 ± 0.02 Gy/GBq (range, 0.03-0.09 Gy/GBq), respectively. Significant uptake and long tumor retention of 177Lu-FAP-2286 resulted in high absorbed tumor doses, such as 3.0 ± 2.7 Gy/GBq (range, 0.5-10.6 Gy/GBq) in bone metastases. No grade 4 adverse events were observed. Grade 3 events occurred in 3 patients-1 with pancytopenia, 1 with leukocytopenia, and 1 with pain flare-up; 3 patients reported a pain response. Conclusion:177Lu-FAP-2286 PTRT, applied in a broad spectrum of cancers, was relatively well tolerated, with acceptable side effects, and demonstrated long retention of the radiopeptide. Prospective clinical studies are warranted.

Prostate-Specific Membrane Antigen Radioligand Therapy Using 177Lu-PSMA I&T and 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: Comparison of Safety, Biodistribution, and Dosimetry.

The objective of this study was to determine the safety, kinetics, and dosimetry of the 177Lu-labeled prostate-specific membrane antigen (PSMA) small molecules 177Lu-PSMA I&T and 177Lu-PSMA-617 in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing PSMA radioligand therapy (PRLT). Methods: In total, 138 patients (mean age, 70 ± 9 y; age range, 46-90 y) with progressive mCRPC and PSMA expression verified by 68Ga-PSMA-11 PET/CT underwent PRLT. Fifty-one patients received 6.1 ± 1.0 GBq (range, 3.4-7.6 GBq) of 177Lu-PSMA I&T, and 87 patients received 6.5 ± 1.1 GBq (range, 3.5-9.0 GBq) of 177Lu-PSMA-617. Dosimetry was performed on all patients using an identical protocol. The mean absorbed doses were estimated with OLINDA software (MIRD Scheme). Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 5.0, of the National Cancer Institute. Results: The whole-body half-lives were shorter for 177Lu-PSMA I&T (35 h) than for 177Lu-PSMA-617 (42 h). The mean whole-body dose of 177Lu-PSMA-617 was higher than that of 177Lu-PSMA I&T (0.04 vs. 0.03 Gy/GBq, P < 0.00001). Despite the longer half-life of 177Lu-PSMA-617, the renal dose was lower for 177Lu-PSMA-617 than for 177Lu-PSMA I&T (0.77 vs. 0.92 Gy/GBq, P = 0.0015). Both PSMA small molecules demonstrated a comparable dose to the parotid glands (0.5 Gy/GBq, P = 0.27). Among all normal organs, the lacrimal glands exhibited the highest mean absorbed doses, 5.1 and 3.7 Gy/GBq, for 177Lu-PSMA-617 and 177Lu-PSMA I&T, respectively. All tumor metastases exhibited a higher initial uptake when using 177Lu-PSMA I&T than when using 177Lu-PSMA-617, as well as a shorter tumor half-life (P < 0.00001). The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&T and 177Lu-PSMA-617 (5.8 vs. 5.9 Gy/GBq, P = 0.96). All patients tolerated the therapy without any acute adverse effects. After 177Lu-PSMA-617 and 177Lu-PSMA I&T, there was a small, statistically significant reduction in hemoglobin, leukocyte counts, and platelet counts that did not need any clinical intervention. No nephrotoxicity was observed after either 177Lu-PSMA I&T or 177Lu-PSMA-617 PRLT. Conclusion: Both 177Lu-PSMA I&T and 177Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. The highest absorbed doses among healthy organs were in the lacrimal and parotid glands-not, however, resulting in any significant clinical sequel. 177Lu-PSMA-617 demonstrated a higher absorbed dose to the whole-body and lacrimal glands but a lower renal dose than did 177Lu-PSMA I&T. The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&T and 177Lu-PSMA-617. There was a large interpatient variability in the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT.

First-in-Humans Study of the SSTR Antagonist 177Lu-DOTA-LM3 for Peptide Receptor Radionuclide Therapy in Patients with Metastatic Neuroendocrine Neoplasms: Dosimetry, Safety, and Efficacy.

The objective of this study was to assess the safety, dosimetry, and efficacy of the 177Lu-labeled somatostatin receptor (SSTR) antagonist DOTA-p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH2 (177Lu-DOTA-LM3) in patients with metastatic neuroendocrine neoplasms (NENs). Methods: Fifty-one patients (aged 27-76 y; mean, 51.6 ± 13.9 y) with metastatic NENs underwent peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-LM3 between August 2017 and December 2019. The median administered activity per cycle was 6.1 ± 0.88 GBq (range, 2.8-7.4 GBq). 68Ga-NODAGA-LM3 PET/CT was used for patient selection and follow-up after 177Lu-DOTA-LM3 PRRT. Morphologic and molecular responses were evaluated in accordance with RECIST 1.1 and the criteria of the European Organisation for Research and Treatment of Cancer (EORTC). Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dosimetry was performed on 11 patients and compared with the SSTR agonist 177Lu-DOTATOC in 247 patients undergoing PRRT on the same dosimetry protocol. Results: Higher uptake and a longer effective half-life were found for 177Lu-DOTA-LM3 than for the agonist 177Lu-DOTATOC in the whole body and in the kidneys, spleen, and metastases, resulting in higher mean absorbed organ and tumor doses. All patients tolerated therapy without any serious acute adverse effects. Mild nausea without vomiting was observed in 5 (9.8%) patients; no other symptoms were reported. The most severe delayed adverse event was Common Terminology Criteria (CTC)-3 thrombocytopenia in 3 (5.9%) patients. Neither CTC-4 thrombocytopenia nor CTC-3-4 anemia or leukopenia was observed after treatment. No significant decline in renal function was observed, nor was hepatotoxicity. According to RECIST 1.1, disease control could be reached in 40 patients (disease control rate, 85.1%) of the 47 patients monitored after 177Lu-DOTA-LM3 PRRT, with a partial response in 17 (36.2%) and stable disease in 23 (48.9%), whereas 7 patients (14.9%) had progressive disease, and by EORTC criteria, there was complete remission in 2 patients (4.3%), partial remission in 21 (44.7%), stable disease in 18 (38.3%), and progressive disease in 6 (12.8%). Conclusion: The antagonist PRRT with 177Lu-DOTA-LM3 could be administered without severe adverse effects and was well tolerated by most patients, with thrombocytopenia occurring in only a few. No other severe adverse effects were observed; in particular, there was no nephrotoxicity. The SSTR antagonist 177Lu-DOTA-LM3 appears to be promising for PRRT, provides a favorable biodistribution and higher tumor radiation doses than SSTR agonists, and was effective in treating advanced metastatic NENs, especially in patients with low or no SSTR agonist binding, even achieving complete remission in some patients.

First-in-Humans Application of 161Tb: A Feasibility Study Using 161Tb-DOTATOC.

161Tb has decay properties similar to those of 177Lu but, additionally, emits a substantial number of conversion and Auger electrons. The aim of this study was to apply 161Tb in a clinical setting and to investigate the feasibility of visualizing the physiologic and tumor biodistributions of 161Tb-DOTATOC. Methods:161Tb was shipped from Paul Scherrer Institute, Villigen-PSI, Switzerland, to Zentralklinik Bad Berka, Bad Berka, Germany, where it was used for the radiolabeling of DOTATOC. In 2 separate studies, 596 and 1,300 MBq of 161Tb-DOTATOC were administered to a 35-y-old male patient with a metastatic, well-differentiated, nonfunctional malignant paraganglioma and a 70-y-old male patient with a metastatic, functional neuroendocrine neoplasm of the pancreatic tail, respectively. Whole-body planar γ-scintigraphy images were acquired over a period of several days for dosimetry calculations. SPECT/CT images were reconstructed using a recently established protocol and visually analyzed. Patients were observed for adverse events after the application of 161Tb-DOTATOC. Results: The radiolabeling of DOTATOC with 161Tb was readily achieved with a high radiochemical purity suitable for patient application. Planar images and dosimetry provided the expected time-dependent biodistribution of 161Tb-DOTATOC in the liver, kidneys, spleen, and urinary bladder. SPECT/CT images were of high quality and visualized even small metastases in bones and liver. The application of 161Tb-DOTATOC was well tolerated, and no related adverse events were reported. Conclusion: This study demonstrated the feasibility of imaging even small metastases after the injection of relatively low activities of 161Tb-DOTATOC using γ-scintigraphy and SPECT/CT. On the basis of this essential first step in translating 161Tb to clinics, further efforts will be directed toward the application of 161Tb for therapeutic purposes.

Prognostic Value of 18F-FDG PET/CT in a Large Cohort of Patients with Advanced Metastatic Neuroendocrine Neoplasms Treated with Peptide Receptor Radionuclide Therapy.

The objective of this retrospective study was to determine the role of 18F-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. Methods: The 495 patients were treated with 177Lu- or 90Y-DOTATOC/DOTATATE PRRT between February 2002 and July 2018. All subjects received both 68Ga-DOTATOC/TATE/NOC and 18F-FDG PET/CT before treatment and were followed 3-189 mo. Kaplan-Meier analysis, log-rank testing (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). Results: One hundred ninety-nine patients (40.2%) presented with pancreatic NENs, 49 with cancer of unknown primary, and 139 with midgut NENs, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8, and in other locations in 42. 18F-FDG PET/CT was positive in 382 (77.2%) patients and negative in 113 (22.8%) before PRRT, whereas 100% were 68Ga-DOTATOC/TATE/NOC-positive. For all patients, the median PFS and OS, defined from the start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive 18F-FDG results predicted shorter PFS (18.5 mo vs. 24.1 mo; P = 0.0015) and OS (53.2 mo vs. 83.1 mo; P < 0.001) than negative 18F-FDG results. Among the cases of pancreatic NENs, the median OS was 52.8 mo in 18F-FDG-positive subjects and 114.3 mo in 18F-FDG-negative subjects (P = 0.0006). For all patients positive for 18F-FDG uptake, and a ratio of more than 2 for the highest SUVmax on 68Ga-somatostatin receptor (SSTR) PET to the most 18F-FDG-avid tumor lesions, the median OS was 53.0 mo, compared with 43.4 mo in those patients with a ratio of less than 2 (P = 0.030). For patients with no 18F-FDG uptake (complete mismatch imaging pattern), the median OS was 108.3 mo versus 76.9 mo for an SUVmax of more than 15.0 and an SUVmax of 15.0 or less on 68Ga-SSTR PET/CT, respectively. Conclusion: The presence of positive lesions on 18F-FDG PET is an independent prognostic factor in patients with NENs treated with PRRT. Metabolic imaging with 18F-FDG PET/CT complements the molecular imaging aspect of 68Ga-SSTR PET/CT for the prognosis of survival after PRRT. High SSTR expression combined with negative 18F-FDG PET/CT results is associated with the most favorable long-term prognosis.

Semiquantitative Parameters in PSMA-Targeted PET Imaging with [18F]DCFPyL: Intrapatient and Interpatient Variability of Normal Organ Uptake.

PURPOSE: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging has impacted the management of patients with prostate cancer (PCa) in many parts of the world. PSMA-targeted endoradiotherapies are also being increasingly utilized and for these applications, the radiopharmaceutical distribution in normal organs is particularly important because it may limit the dose that can be delivered to tumors. In this study, we measured both interpatient and intrapatient variability of [18F]DCFPyL uptake in the most relevant normal organs. PROCEDURES: Baseline and 6-month follow-up PSMA-targeted [18F]DCFPyL PET/computed tomography (CT) scans from 39 patients with PCa were reviewed. Volumes of interest were manually drawn using the best visual approximation of the organ edge for both lacrimal glands, all four major salivary glands, the liver, the spleen, and both kidneys for all patients. The average SUVmean, the COVs, and intraclass correlation coefficients (ICCs) across scans were calculated. Bland-Altman analyses were performed for all organs to derive repeatability coefficients (RCs). RESULTS: The liver demonstrated the lowest interpatient variability (13.0 and 16.6 % at baseline and follow-up, respectively), while the spleen demonstrated the largest interpatient variability (44.6 and 51.0 % at baseline and follow-up, respectively). The lowest intrapatient variability was found in the spleen (ICC 0.86) while the highest intrapatient variability was in the kidneys (ICCs 0.40-0.50). Bland-Altman analyses showed 95 % repeatability coefficients for mean uptake > 40 % for multiple organs and were highest for the lacrimal glands, kidneys, and spleen. CONCLUSIONS: Normal organs demonstrate significant variability in uptake of the PSMA-targeted radiotracer [18F]DCFPyL. Depending on the organ, different contributions of interpatient and intrapatient factors affect the intrinsic variability. The RCs also vary significantly among the different organs were highest for the lacrimal glands, kidneys, and spleen. These findings may have important implications for the design of clinical protocols and personalized dosimetry for PSMA-targeted endoradiotherapies.

From Bench to Bedside-The Bad Berka Experience With First-in-Human Studies.

Precision oncology is being driven by rapid advances in novel diagnostics and therapeutic interventions, with treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations. Inherent in the theranostics paradigm is the assumption that diagnostic test results can precisely determine whether an individual is likely to benefit from a specific treatment. As part and integral in the current era of precision oncology, theranostics in the context of nuclear medicine aims to identify the appropriate molecular targets in neoplasms (diagnostic tool), so that the optimal ligands and radionuclides (therapeutic tool) with favorable labeling chemistry can be selected for personalized management of a specific disease, taking into consideration the specific patient, and subsequently monitor treatment response. Over the past two decades, the use of gallium-68 labeled peptides for somatostatin receptor (SSTR)-targeted PET/CT (or PET/MRI) imaging followed by lutetium-177 and yttrium-90 labeled SSTR-agonist for peptide receptor radionuclide therapy has demonstrated remarkable success in the management of neuroendocrine neoplasms, and paved the way to other indications of theranostics. Rapid advances are being made in the development of other peptide-based radiopharmaceuticals, small molecular-weight ligands and with newer radioisotopes with more favorable kinetics, potentially useful for theranostics strategies for the clinical application. The present review features the Bad Berka experience with first-in-human studies of new radiopharmaceuticals, for example, prostate-specific membrane antigen ligand, gastrin-releasing peptide receptor, neurotensin receptor 1 ligand, novel SSTR-targeting peptides and nonpeptide, and bone-seeking radiopharmaceuticals. Also new radioisotopes, for example, actinium (225Ac), copper (64Cu), scandium (44Sc), and terbium (152Tb/161Tb) will be discussed briefly demonstrating the development from basic science to precision oncology in the clinical setting.

177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer Patients with a Single Functioning Kidney.

The aim of this study was to assess the safety, tolerability, and effects on renal function as well as therapeutic efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) using 177Lu-labeled PSMA-617 in patients with metastatic castration-resistant prostate cancer and a single functioning kidney before PRLT. Methods: Sixteen patients (aged 53-78 y; mean age, 64.7 ± 6.5 y) with a single functioning kidney received PRLT with 177Lu-PSMA-617 between March 2015 and October 2018. All parameters of renal function (serum creatinine, blood urea nitrogen, and electrolytes) were prospectively documented in a structured database and analyzed before each PRLT cycle and in follow-up. Renal function was further quantified by measuring tubular extraction rate (TER) using 99mTc-mercaptoacetyltriglycine renal scintigraphy. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Kaplan-Meier analysis was performed to obtain the progression-free survival and overall survival. Results: The median administered activity was 22.1 GBq (range, 15.4-33.8 GBq). The calculated absorbed radiation dose to the kidney per cycle was 5.3 ± 2.1 Gy (0.81 ± 0.32 Gy/GBq). Renal function was already impaired at baseline in 43.7% of patients, including CTCAE grade 1 renal impairment in 25.0% and CTCAE grade 2 in 18.8%. Grade 1 and 2 renal impairment, respectively, were present in 37.5% and 6.3% of the patients after the first PRLT cycle and in 31.3% and 12.5% after the second cycle. No CTCAE grade 3 or 4 nephrotoxicity was observed during or after treatment. There was no significant change in either TER or the ratio of TER to lower-limit TER after the last cycle of treatment (P > 0.05). The median PFS was 8.1 mo based on both the criteria of the European Organization for Research and Treatment of Cancer and RECIST. The median overall survival has yet to be reached with a median follow-up time of 19.3 mo (range, 5.8-45.3 mo). Conclusion: In patients with a single functioning kidney, 177Lu-PSMA-617 PRLT is feasible, seems to be effective, and is well tolerated, without any signs of acute or subacute nephrotoxicity during a mean follow-up of nearly 2 y (and up to 45.3 mo). Further long-term follow-up of this special patient group is warranted.

Theranostics of prostate cancer: from molecular imaging to precision molecular radiotherapy targeting the prostate specific membrane antigen.

Alterations at the molecular level are a hallmark of cancer. Prostate cancer is associated with the overexpression of prostate-specific membrane antigen (PSMA) in a majority of cases, predominantly in advanced tumors, increasing with the grade or Gleason's score. PSMA can be selectively targeted using radiolabeled PSMA ligands. These small molecules binding the PSMA can be radiolabeled with γ-emitters like 99mTc and 111In or positron emitters like 68Ga and 18F for diagnosis as well as with their theranostic pairs such as 177Lu (ß-emitter) or 225Ac (α-emitter) for therapy. This review summarizes the theranostic role of PSMA ligands for molecular imaging and targeted molecular radiotherapy, moving towards precision oncology.

Injection of Botulinum Toxin for Preventing Salivary Gland Toxicity after PSMA Radioligand Therapy: an Empirical Proof of a Promising Concept.

The dose-limiting salivary gland toxicity of 225Ac-labelled PSMA for treatment of metastatic, castration-resistant prostate cancer remains unresolved. Suppressing the metabolism of the gland by intraparenchymal injections of botulinum toxin appears to be a promising method to reduce off-target uptake. A 68Ga-PSMA PET/CT scan performed 45 days after injection of 80 units of botulinum toxin A into the right parotid gland in a 63-year-old patient showed a decrease in the SUVmean in the right parotid gland of up to 64% as compared with baseline. This approach could be a significant breakthrough for radioprotection of the salivary glands during PSMA radioligand therapy.

177Lu-3BP-227 for Neurotensin Receptor 1-Targeted Therapy of Metastatic Pancreatic Adenocarcinoma: First Clinical Results.

Neurotensin receptor 1 (NTR1) is overexpressed in ductal pancreatic adenocarcinoma, which is still one of the deadliest cancers, with a very poor prognosis. Eligible patients were offered salvage radiopharmaceutical therapy with the novel NTR1 antagonist 177Lu-3BP-227. Methods: Six patients with confirmed ductal pancreatic adenocarcinoma who had exhausted all other treatment options received 177Lu-3BP-227 for evaluation of NTR1 expression in vivo. Three patients received treatment activities of 5.1-7.5 GBq. Results: Administration of 177Lu-3BP-227 was well tolerated by all patients. The kidneys were identified as the dose-limiting organ. The most severe adverse event was reversible grade 2 anemia. One patient achieved a partial response and experienced significant improvement of symptoms and quality of life. This patient survived 13 mo from diagnosis and 11 mo from the start of 177Lu-3BP-227 therapy. Conclusion: This initial report provides clinical evidence of the feasibility of treatment of ductal pancreatic adenocarcinoma using 177Lu-3BP-227.

PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013.

A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with 68Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with 177Lu-PSMA ligands. 68Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring. Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved.

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25-29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 µg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 µg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1-3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably.

177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy.

UNLABELLED: The objective of this study was to analyze the safety and efficacy of the (177)Lu-labeled DOTAGA-based prostate-specific membrane antigen (PSMA) ligand (177)Lu-DOTAGA-(I-y)fk(Sub-KuE) ((177)Lu-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Fifty-six mCRPC patients underwent PSMA radioligand therapy (RLT) with (177)Lu-PSMA. (68)Ga-PSMA-(N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) ((68)Ga-PSMA) PET/CT was used for patient selection and follow-up after PSMA RLT. Hematologic status, renal function, and serum prostate-specific antigen levels were documented before and after therapy. Dosimetry was performed in 30 patients. RESULTS: (177)Lu-PSMA demonstrated high absorbed tumor doses (median, 3.3 mGy/MBq) compared with the levels in normal organs. Parotid glands received higher doses (1.3 mGy/MBq) than kidneys (0.8 mGy/MBq). All patients tolerated the therapy without any acute adverse effects. Except for mild reversible xerostomia in 2 patients, no long-term side effects were observed. There was a small but statistically significant reduction in erythrocyte and leukocyte counts; only the reduction in erythrocyte counts decreased slightly below the reference range. No thrombocytopenia occurred. The severity of pain was significantly reduced in 2 of 6 patients (33.3%). A decrease in prostate-specific antigen levels was noted in 45 of 56 patients (80.4%). Of 25 patients monitored for at least 6 mo after 2 or more PSMA RLT cycles, a molecular response evaluation ((68)Ga-PSMA PET/CT) revealed partial remission in 14, stable disease in 2, and progressive disease in 9 patients. Contrast-enhanced CT revealed partial remission in 5, stable disease in 13, and progressive disease in 7 patients. The median progression-free survival was 13.7 mo, and the median overall survival was not reached during follow-up for 28 mo. CONCLUSION: PSMA RLT with (177)Lu-PSMA is feasible, safe, and effective in end-stage progressive mCRPC with appropriate selection and follow-up of patients by (68)Ga-PSMA PET/CT through application of the concept of theranostics.