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Introduction: Carcinoid syndrome is the most frequent functional syndrome of neuroendocrine neoplasia. It is characterized by flushing, diarrhea, wheezing, hypotension, and exanthema and may cause carcinoid heart disease. Methods: We assessed clinical characteristics and prognosis of patients with carcinoid syndrome and carcinoid heart disease in 276 patients from 3 referral centers. Results: Carcinoid syndrome patients had a mean age of 57 years (range 21–84) and a normal BMI of 24.9 (SD 4.5; range 13.8–39.6). Most primaries were of small bowel or unknown primaries with distant metastasis in 94.6%. Flushing was the most frequent symptom in 74.3% of patients, followed by diarrhea in 68.8%, and wheezing in 40.9%. Pain was described by 45.3%, weakness by 23.5%, and weight loss of >10% in 6 months by 30.1% of patients. Carcinoid heart disease was diagnosed in 37.3% of patients (n = 104) by echocardiography and involved predominantly in the tricuspid valve. Combinations with other valve defects were common. Somatostatin analogs were taken by 80.4% of patients and 17% needed additional loperamide/opium tincture. Surgery and peptide receptor radiotherapy were most frequent treatments. The median survival of patients with carcinoid syndrome after diagnosis was 9 years. Prognosis was significantly impaired by male sex and diagnosis of carcinoid heart disease but surprisingly significantly increased by the presence of symptoms flushing and weakness. Discussion/Conclusion: Carcinoid syndrome is associated with extensive disease and primaries in small bowels or of unknown primary. Weight loss, weakness, and pain are frequent, and carcinoid heart disease is diagnosed in more than one-third of patients.

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-human results using 177Lu-FAP-2286 for peptide-targeted radionuclide therapy (PTRT). Methods: PTRT using 177Lu-FAP-2286 was performed in 11 patients with advanced adenocarcinomas of pancreas, breast, rectum and ovary after prior confirmation of uptake on 68Ga-FAP-2286/-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 doses were 0.07 ± 0.02 Gy/GBq (range 0.04 – 0.1). The mean absorbed doses for kidneys and red marrow were 1.0 ± 0.6 Gy/GBq (range 0.4 – 2.0) and 0.05 ± 0.02 Gy/GBq (range 0.03 – 0.09), respectively. Significant uptake and long tumor retention of 177Lu-FAP-2286 resulted in high absorbed tumor doses, e.g., 3.0 ± 2.7 Gy/GBq (range 0.5 – 10.6) in bone metastases. No grade (G) 4 adverse events were observed. G3 events occurred in 3 patients – 1 pancytopenia, 1 leukocytopenia and 1 pain flare-up; 3 patients reported 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 (PSMA)-based radioligand therapy (RLT) showed in a multicentre WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) study that the presence of bone metastases is a negative prognosticator for the survival. The current multicentre retrospective analysis aims to evaluate the response rate to RLT, the overall survival (OS) of patients and the safety of the treatment according to the extent of bone involvement. The study included patients with progressive metastatic castration-resistant prostate cancer (mCRPC), who underwent RLT with [177Lu]Lu-PSMA-617 and a follow-up of at least 6 months. Tumour burden in the bone was classified prior to RLT as follows: less than 6 lesions, 6–20 lesions, more than 20 lesions and diffuse involvement. The response rate was evaluated using changes of the prostate-specific antigen (PSA) after the first treatment cycle. Overall survival was calculated from the date of the first treatment. Haematological adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. A total of 319 males were included in the analysis. The extent of bone metastases and PSA response did not correlate significantly. Any PSA decline was observed in 73% patients; 44% showed a decline of ≥50%. The median OS of patient in the different subgroups was 18 months (less than 6 lesions), 13 months (6–20 lesions), 11 months (more than 20 lesions) and 8 months (diffuse involvement), respectively (p

We report the impact of 177Lu-DOTATATE treatment on abdominal pain, diarrhea, and flushing, symptoms that patients with advanced midgut neuroendocrine tumors often find burdensome. Methods: All patients enrolled in the international randomized phase 3 Neuroendocrine Tumors Therapy (NETTER-1) trial (177Lu-DOTATATE plus standard-dose octreotide long-acting repeatable [LAR], n = 117; high-dose octreotide LAR, n = 114) were asked to record the occurrence of predefined symptoms in a daily diary. Change from baseline in symptom scores (mean number of days with a symptom) was analyzed using a mixed model for repeated measures. Results: Patients (intent-to-treat) who received 177Lu-DOTATATE experienced a significantly greater decline from baseline in symptom scores than patients who received high-dose octreotide LAR. For 177Lu-DOTATATE, the mean decline in days with abdominal pain, diarrhea, and flushing was 4.10, 4.55, and 4.52 d per 4 wk, respectively, compared with 0.99, 1.44, and 2.54 d for high-dose octreotide LAR. The mean differences were 3.11 d (95% CI, 1.35–4.88; P = 0.0007) for abdominal pain, 3.11 d (1.18–5.04; P = 0.0017) for diarrhea, and 1.98 d (0.08–3.88; P = 0.0413) for flushing, favoring 177Lu-DOTATATE. A positive repeated-measures correlation was found between diary-recorded symptom scores and questionnaire-recorded pain, diarrhea, and flushing. Conclusion: In addition to efficacy and quality-of-life benefits, symptom diaries from NETTER-1 demonstrated that treatment with 177Lu-DOTATATE was associated with statistically significant reductions in abdominal pain, diarrhea, and flushing, constituting the core symptoms of patients with progressive midgut neuroendocrine tumors, compared with high-dose octreotide LAR, supporting a beneficial effect of 177Lu-DOTATATE on health-related quality of life. Title in Web of Science: Symptom Diaries of Patients with Midgut Neuroendocrine Tumors Treated with Lu-177-DOTATATE

The objective of this study was to assess the safety, dosimetry, and efficacy of the (177)Lu-labeled somatostatin receptor (SSTR) antagonist DOTA-p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH(2) ((177)Lu-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 (177)Lu-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). (68)Ga-NODAGA-LM3 PET/CT was used for patient selection and follow-up after (177)Lu-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 (177)Lu-DOTATOC in 247 patients undergoing PRRT on the same dosimetry protocol. Results: Higher uptake and a longer effective half-life were found for (177)Lu-DOTA-LM3 than for the agonist (177)Lu-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 (177)Lu-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 (177)Lu-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 (177)Lu-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.

The objective of this retrospective study was to determine the role of F-18-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 Lu-177- or Y-90-DOTATOC/DOTATATE PRRT between February 2002 and July 2018. All subjects received both Ga-68-DOTATOC/TATE/NOC and F-18-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. F-18-FDG PET/CT was positive in 382 (77.2%) patients and negative in 113 (22.8%) before PRRT, whereas 100% were Ga-68-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 F-18-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

Introduction The impact of prior therapies, especially chemotherapy, on overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) receiving [177Lu]Lu-PSMA-617 therapy has been the subject of controversy. Therefore, WARMTH decided to plan a multicenter retrospective analysis (the “617 trial”) to evaluate response rate and OS as well as the impact of prior therapies on OS in more than 300 patients treated with 177Lu-PSMA-617. Materials and methods The data of 631 metastatic CRPC (mCRPC) patients from 11 different clinics were evaluated. According to the inclusion and exclusion criteria, all patients had to have received at least abiraterone or enzalutamide prior to [177Lu]Lu-PSMA-617 therapy. The patients were divided into three groups: patients who had received prior chemotherapy, patients who avoided chemotherapy, and patients for whom a chemotherapy was contraindicated. Results The analysis included the data of 416 patients, with a median age of 71.9 years. At the time of analysis, 87 patients (20,9%) were still alive. A total of 53.6% of patients had received both abiraterone and enzalutamide; 75.5% and 26.4% had a history of chemotherapy with docetaxel and cabazitaxel, respectively. A total of 20.4% had had Ra-223. The median OS was 11.1 months. Prior chemotherapy, the existence of bone and liver metastases, as well as Eastern Cooperative Oncology Group (ECOG) status, were significant prognosticators of worse overall survival in both univariate and multivariate analyses. Patients without any prior chemotherapy showed a significantly longer OS (14.6 months). The median OS in patients who received one or two lines of chemotherapy with docetaxel or docetaxel followed by cabazitaxel, respectively, was 10.9 months and 8.9 months. There was no difference in OS between patients who had not received chemotherapy and patients for whom chemotherapy was contraindicated. The other prior therapies did not have any significant impact on OS. Conclusion In the present multicenter analysis, chemotherapy-naïve mCRPC patients receiving [177Lu]Lu-PSMA-617 therapy had a significantly longer OS than patients with a history of chemotherapy. This remained independent in the multivariate analysis besides presence of bone and liver metastases as negative prognosticators for survival, whereas an ECOG of 0–1 is associated with a longer OS.

Radiolabeled somatostatin analogs for somatostatin receptor (SSTR)-targeted imaging and peptide receptor radionuclide therapy (PRRT) have demonstrated remarkable success in the management of SSTR-expressing neuroendocrine neoplasms. Primary neuroendocrine breast carcinoma is rare. Heterogeneous SSTR overexpression has also been documented in breast cancer, in both human breast cancer specimens and clinical studies. We report here a case of a 69-year-old woman who had both breast invasive ductal carcinoma and primary large-cell neuroendocrine breast carcinoma (Ki-67 proliferation index of 20%), with disseminated bone and lymph node metastases, demonstrating exceptional tracer uptake on Ga-DOTATOC PET/CT, and remarkably partial remission after Lu-DOTATOC PRRT.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is usually efficient subsequent to treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy, NETest monitors disease. We prospectively evaluated: 1) NETest as a surrogate biomarker for RECIST; 2) The correlation of NETest levels with PPQ prediction. METHODS: Three independent (177)Lu-PRRT-treated GEP-NET and lung cohorts (Meldola, Italy: n=72; Bad-Berka, Germany: n=44; Rotterdam, Netherlands: n=41). Treatment response: RECIST1.1 [Responder (stable, partial and complete response) vs Non-Responder]. Blood sampling: pre-PRRT, before each cycle and follow-up (2-12 months). PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable≤40; progressive >40). CgA (ELISA) as comparator. Samples deidentified, measurement and analyses blinded. Kaplan-Meier survival and standard statistics. RESULTS: 122 of the 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p40 (progressive) vs stable (≤40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04 (95%CI: 0.02-0.07). PPQ response prediction was accurate in 118 (97%) with a 99% accurate positive and 93% accurate negative prediction. NETest significantly (p97%) with the pretreatment PPQ response predictor. CgA was non-informative.

Somatostatin receptor-targeted α-therapy using α-emitter 225Ac-labeled somatostatin analogs has been suggested as a treatment option in advanced metastatic neuroendocrine tumors (NETs) failing treatment with β-emitters, such as 177Lu or 90Y. Thymus NETs are rare and usually more aggressive than other neuroendocrine tumor entities. We present here a case with β-radiation refractory metastatic thymus NET, who demonstrated an excellent therapy response (molecular and morphological remission, as well as significantly improved clinical symptoms) after 225Ac-DOTATOC-targeted α-therapy, without any adverse effects during the treatment or in the follow-up period.

PSMA based radioligand is a new investigational drug for treatment of metastatic multidrug-resistant and castration-resistant prostate cancer. Prognostic factors point to above and below average overall survival (OS) after the treatment. Kessel et al. [Theranostics 2019;9:4841-8] reported for the first time that two sites of visceral metastases, lungs and liver, differed in impact on OS after treatment with 177Lu PSMA 617. Treatment with established drugs showed the same trend. The difference in OS between the sites is independent of the type of treatment and can reflect changes in tumor biology during the progression of metastatic prostate cancer.

We report here the 12-year survival after the first peptide receptor radionuclide therapy (PRRT) of a patient with metastatic rectal neuroendocrine neoplasms, who received 7 cycles of PRRT with Lu/Y-DOTATATE/DOTATOC in 4 treatment phases. The patient demonstrated excellent response to each cycle of treatment, without any adverse effect even after repeated PRRT cycles. Most recently, immunohistochemistry revealed a G3 neuroendocrine neoplasm and intraspinal metastasis were successfully resected by neurosurgical intervention. This case nicely demonstrates that several "salvage" PRRTs can be given over many years leading to repetitive benefit for the patient and saving patients of possible toxicity of alternative treatments.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for patients with neuroendocrine neoplasms. The aim of this study was to identify clinical and treatment parameters associated with progression-free survival (PFS) and overall survival (OS). Methods: All patients treated from October 2002 until March 2016 at the Zentralklinik Bad Berka with at least 3 administrations of PRRT (maximal interval of 6 mo between consecutive administrations) were included. Data were collected in 5 categories: general patient characteristics, tumor characteristics, prior treatments, radioisotope used for PRRT, and blood chemistry. Survival was analyzed using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were performed to identify parameters associated with PFS and OS. Results: In total, 782 patients were included, with a median follow-up of 36 mo. The median PFS and OS were 22 and 53 mo, respectively. Parameters associated with lower PFS in the multivariate analysis were a Ki-67 of more than 5%, previous treatment with interferon-alpha and chemotherapy, presence of diabetes, and chromogranin-A (CgA) levels higher than 336 mu g/L. Parameters associated with lower OS were a Ki-67 of more than 10%, performance status of at least 1, previous chemotherapy and ablation, and CgA levels higher than 112 mu g/L. Conclusion: Higher Ki-67 values, as well as higher CgA levels and previous chemotherapy, had a negative outcome on both PFS and OS. Furthermore, PFS was negatively associated with previous interferon-alpha treatment and diabetes, whereas lower OS was related to prior ablation and higher performance status.

Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (177Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an "unproven intervention in clinical practice", in accordance with the best currently available knowledge.

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 [(18)F]DCFPyL uptake in the most relevant normal organs. PROCEDURES: Baseline and 6-month follow-up PSMA-targeted [(18)F]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 SUV(mean), 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 [(18)F]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.

Background Patients with neuroendocrine tumors (NETs) of the gastrointestinal tract suffer frequently from chronic diarrhea. A well characterized medical advice containing zeolite (Detoxsan® powder) was applied to patients suffered from therapy-refractory diarrhea either by its frequency or by watery stool, despite receiving standard pharmacotherapy according to the guidelines for carcinoid syndrome and comorbidities. Detoxsan® powder acts as an adsorbent and might reduce significantly symptoms of diarrhea in patients suffering from NETs. Aim To overcome the therapy-refractory diarrhea of patients with NETs by the zeolite containing medical advice Detoxsan® powder. Methods A total of 20 patients (12 female and 8 male) suffering from diarrhea either by its frequency or from watery stool caused by NETs were included. In each patient, the diagnosis had been confirmed by histology and somatostatin receptors expression proven by positron emission tomography/computed tomography using Ga-68-labeled somatostatin analogs. All patients received standard-of-care pharmacotherapy and were additionally given Detoxsan® powder as an extemporaneous drug containing 90% natural Cuban zeolite and 10% magnesium aspartate. Recommended daily dosage ranges between 3 g once to three times per day. Each day dose and bowel movements were documented by the patients themselves in a pre-defined table. Additionally to the bowel movements quantitative determinations of serotonin, urea, creatinine and single ions were performed within the serum of the patients by commercially available equipment used as a matter of routine in the clinic. Results All patients enrolled in this pilot study did not only suffer from NETs, but also from comorbidities and treatment-resistant diarrhea. There was insufficient control of diarrhea, most probably due to the secretion of hormones like serotonin produced by the slowly growing and highly differentiated NETs. All patients only took Detoxsan® powder as an antidiarrheal drug. In general, response effects need several days to become perceptible and require an intake of Detoxsan® powder for an extended time period or intermittently, if persisting stabilization of bowel movements could not be achieved. A correlation between NET grade, part and size of bowel resection and functionality of the tumor could not be demonstrated. Therefore, diarrhea seemed to be based on the metabolic activity of the well-differentiated NETs, which eventually led to treatment resistance. In summary, 14 out of the 20 patients (70%) declared to be very content with using Detoxsan® powder and observed a significant reduction of diarrhea, while the effective dose and intake period that resulted in a symptom relief varied individually. Conclusion Detoxsan® powder is able to reduce significantly symptoms of NET-related diarrhea in the majority of patients. The duration of taking Detoxsan® powder and its dosage vary individually.

177Lu-PSMA radioligand therapy (LuPRLT) is mainly used for patients with metastatic castration-resistant prostate cancer who are resistant to established drugs. This study describes LuPRLT, either LuPSMA I&T or LuPSMA RLT-617, for 45 patients with predominant lymph node metastatic prostate cancer (LNM PC). Thirty-five patients had LNM and ten patients had LNM and one or two bone metastases. Before LuPRLT, the patients had prostate specific antigen (PSA) of median 18 µg/l (interquartile range (IQR): 3.3–39). LuPRLT was given with a cumulative injected 177Lu activity of median 14.5 GBq (IQR: 12.2–20.4). Maximum percentage decline of PSA was median 92% (IQR: 70–99). Thirty-five patients with only LNM had a better overall survival (OS) than ten patients with LNM and one or two bone metastases. Thirty-three docetaxel-naïve patients had a longer PSMA PET/CT progression-free survival than twelve patients who were resistant to docetaxel. Twenty-two patients who received LuPRLT with a cumulative injected 177Lu activity ≥ 14.8 GBq had a better PSMA PET/CT progression-free survival than 23 patients who received LuPRLT with a lower cumulative injected 177Lu activity. Seventeen patients with relapse after LuPRLT who received rechallenge LuPRLT or ActPRLT had a better OS than five patients who received other forms for relapse treatment. LuPRLT gave mild and transitory adverse effects. The findings of the present study suggest that LuPRLT of patients with LNM may be effective and safe. The promising results motivate randomized phase II trials to further quantify the impact of LuPRLT as treatment of patients with LNM.

OBJECTIVE The aim of the study was to compare impact on survival after resection of primary tumors (PTs) after peptide receptor radionuclide therapy (PRRT). BACKGROUND PRRT is a highly effective therapeutic option to treat locally advanced or metastatic neuroendocrine neoplasms (NENs). METHODS We retrospectively analyzed the data of 889 patients with advanced NEN (G1-G3, stage IV) treated with at least 1 cycle of PRRT. In 486 of 889 patients (55%, group 1), PT had been removed before PRRT. Group 2 constituted 403 patients (45%) with no prior PT resection. Progression-free survival (PFS) and overall survival (OS) was determined by 68Ga SSTR-PET/CT in all patients applying RECIST and EORTC. RESULTS Most patients had their PT in pancreas (n = 335; 38%) and small intestine (n = 284; 32%). Both groups received a mean of 4 cycles of PRRT (P = 0.835) with a mean cumulative administered radioactivity of 21.6 ± 11.7 versus 22.2 ± 11.2 GBq (P = 0.407). Median OS in group 1 was 134.0 months [confidence interval (CI): 118-147], whereas OS in group 2 was 67.0 months (CI: 60-80; hazard ratio 2.79); P < 0.001. Likewise, the median progression-free survival after first PRRT was longer in group 1 with 18.0 (CI: 15-20) months as compared to group 2 with 14.0 (CI: 15-18; hazard ratio 1.21) months; P = 0.012. CONCLUSIONS A previous resection of the PT before PRRT provides a significant survival benefit in patients with NENs stage IV.

Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy using PSMA-617 and PSMA-I&T ligands (Lu-177-PRLT) is an emerging treatment in metastatic castration-resistant prostate cancer (mCRPC). This retrospective study evaluates clinical outcomes of Lu-177-PRLT in earlier and later phases of mCRPC grouped by previous taxane chemotherapy. Methods: A retrospective analysis was performed on 167 patients with mCRPC who underwent Lu-177-PRLT between March 2013 and December 2016. Patients were classified as either taxane chemotherapy pretreated (T-pretreated) or naive (T-naive) depending on whether they had received taxane-based chemotherapy prior to Lu-177-PRLT. Clinical outcome for T-pretreated and T-naive patients was assessed by overall survival (OS), radiographic progression-free survival, and prostate-specific antigen (PSA) response rate. Univariate and multivariable analyses were performed for both T-pretreated and T-naive patients to determine predictors of outcome. Toxicity was categorized by the Common Terminology Criteria for Adverse Events (version 4.03). Results: Of the 167 patients treated with Lu-177-PRLT, 83 were T-pretreated and 84 were T-naive. At baseline, T-pretreated patients had overall poorer performance status, a higher prevalence of bone metastases, higher PSA levels, lower hemoglobin levels, higher alkaline phosphatase (ALP) levels and had received more additional therapies compared with T-naive patients. Median OS was 10.7 mo for T-pretreated patients and 27.1 mo for T-naive patients. Median radiographic progression-free survival was 6.0 mo for T-pretreated patients and 8.8 mo for T-naive patients. PSA response assessment was evaluable in 132 patients and seen in 25 of 62 (40%) T-pretreated patients and 40 of 70 (57%) T-naive patients. Significant determinates of inferior OS in multivariable analysis for T-pretreated patients were poorer performance status, lower cumulative administered activity, and lower baseline hemoglobin. Higher baseline alkaline phosphatase was the only significant determinate of inferior OS in multivariable analysis for T-naive patients. Overall Lu-177-PRLT was safe, with minimal adverse effects evident during follow-up in both T-pretreated and T-naive patients. Conclusion: Lu-177-PRLT is a promising therapy in mCRPC, with encouraging outcomes and minimal associated toxicity seen in both our T-naive and heavily pretreated patient cohorts.

The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of 177Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ≥ 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT.

We present here a case with β-radiation-refractory metastatic neuroendocrine tumors, who demonstrated an excellent therapy response after 1 cycle of Ac-DOTATOC, without any significant adverse effects even after 10 cycles of β-emitter peptide receptor radionuclide therapy followed by α-peptide receptor radionuclide therapy.

Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues has been proven to be very useful in the management of advanced, well-differentiated neuroendocrine neoplasms (NENs). We present here the pregnancy outcome in a NEN patient, who naturally conceived and gave birth to a healthy baby, after 4 cycles of PRRT administering a cumulative radioactivity of 27.1 GBq. This case underlines that pregnancy and birth without sequelae are possible in patients with NEN who have been treated with PRRT and offers a definitive prospect for patients of reproductive age group who plan conception despite having received or due to undergo PRRT.

Prostate cancer is the second leading cause of cancer death for men in many parts of the world. Radical prostatectomy (RP) and external beam radiotherapy (EBRT) are effective treatment of localized prostate cancer but many patients recur with raising levels of prostate-specific antigen (PSA). Localized salvage therapies for suspected local failure such as salvage EBRT after RP are most effective during early PSA recurrence. In a Danish national cohort study, salvage EBRT for patients with PSA recurrence after RP undertaken without restaging imaging was effective for approximately half of the patients [1]. Improving on these results requires identification of men with truly localized or oligometastatic recurrence. However, restaging with conventional imaging such as CT and bone scans has limitations. For example, among patients with PSA recurrence after RP, those with a rising PSA

// Richard P. Baum 1 , Harshad R. Kulkarni 1 , Aviral Singh 1 , Daniel Kaemmerer 2 , Dirk Mueller 1 , Vikas Prasad 3 , Merten Hommann 2 , Franz C. Robiller 4 , Karin Niepsch 1 , Holger Franz 5 , Arthur Jochems 6 , Philippe Lambin 6, 7 and Dieter Horsch 8 1 THERANOSTICS Center for Molecular Radiotherapy, Zentralklinik Bad Berka GmbH, Bad Berka, Germany 2 Department of General and Visceral Surgery, Zentralklinik Bad Berka GmbH, Bad Berka, Germany 3 Clinic for Nuclear Medicine, Charite, Berlin, Germany 4 Center of Molecular Imaging, Zentralklinik Bad Berka GmbH, Bad Berka, Germany 5 Lohmann and Birkner, Berlin, Germany 6 Department of Radiology, GROW - School for Oncology and Developmental Biology, Maastricht University Hospital, Maastricht, The Netherlands 7 Department of Radiation Oncology (The D-Lab), GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands 8 Department of Gastroenterology/Endocrinology, Center for Neuroendocrine Tumors Bad Berka – ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany Correspondence to: Dieter Horsch, email: dieter.hoersch@zentralklinik.de Keywords: peptide receptor radionuclide therapy; neuroendocrine tumors; survival; functional syndromes Received: November 11, 2017 Accepted: February 01, 2018 Epub: February 15, 2018 Published: March 30, 2018 ABSTRACT Introduction: Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. Methods: In our center, 2294 patients were screened between 2004 and 2014 by 68 Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90 Yttrium or 177 Lutetium-based PRRT. Progression free survival was determined by 68 Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. Results: Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. Conclusion: PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68 Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy.

Prostate cancer with neuroendocrine differentiation is associated with a poor prognosis, rapid disease progression, and treatment resistance, and constitutes a diagnostic and therapeutic dilemma. We present images of Lu-DOTATATE scan and Ga-DOTATATE PET/CT scan conducted on a 65-year-old man with prostate cancer with neuroendocrine differentiation, whose disease progressed despite conventional treatment and Lu-PSMA radioligand therapy; however, an extraordinary radiographic tumor remission, biochemical response, and improvement of clinical symptoms were observed after the patient underwent Lu-DOTATATE peptide receptor radionuclide therapy.

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.

Gastrin-releasing peptide receptors (GRPRs) represent attractive targets for cancer diagnosis and therapy owing to their overexpression in widespread human tumors. Bombesin (BBN) analogues coupled to suitable chelators for stable radiometal binding have been proposed for diagnostic imaging and radionuclide therapy (theranostics) of GRPR-positive tumors. Recently, interest has shifted from BBN-like receptor agonists to GRPR-radioantagonists, because radioantagonists do not induce adverse effects after injection to patients and display superior pharmacokinetic in vivo profiles. Thus, they seem more advantageous for clinical use compared to agonists. Newer developments highlighting the theranostic potential of GRPR-radioantagonists in cancer patient management are presented herein.

44Sc is a promising positron emission tomography (PET) radionuclide (T1/2 = 4.04 hours, Eβ+average = 632 keV) and can be made available, using a cyclotron production route, in substantial quantities as a highly pure product. Herein, the authors report on a first-in-human PET/CT study using 44Sc-DOTATOC prepared with cyclotron-produced 44Sc. The production of 44Sc was carried out through the 44Ca(p,n)44Sc nuclear reaction at Paul Scherrer Institut, Switzerland. After separation, 44Sc was shipped to Zentralklinik Bad Berka, Germany, where radiolabeling was performed, yielding radiochemically pure 44Sc-DOTATOC. Two patients, currently followed up after peptide receptor radionuclide therapy of metastatic neuroendocrine neoplasms, participated in this proof-of-concept study. Blood sampling was performed before and after application of 44Sc-DOTATOC. PET/CT acquisitions, performed at different time points after injection of 44Sc-DOTATOC, allowed detection of even very small lesions on delayed scans. No clinical adverse effects were observed and the laboratory hematological, renal, and hepatic profiles remained unchanged. In this study, cyclotron-produced 44Sc was used in the clinic for the first time. It is attractive for theranostic application with 177Lu, 90Y, or 47Sc as therapeutic counterparts. 44Sc-based radiopharmaceuticals will be of particular value for PET facilities without radiopharmacy, to which they can be shipped from a centralized production site.

Prostate cancer is the most common noncutaneous cancer among men, rendering the diagnosis and staging of significant medical and public interest. One of the most interesting developments in the application of nuclear oncology has been the development of novel diagnostic agents that are able to facilitate targeted therapies using the concept of theranostics. This review summarizes the current and emerging molecular imaging techniques for the investigation of patients with prostate cancer with emphasis on the potential of 64Cu-PSMA PET/CT in staging, restaging, and the application of theranostics.

Lu-177-labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castration resistant prostate cancer (mCRPC). Initiated by the German Society of Nuclear Medicine, a retrospective multicenter data analysis was started in 2015 to evaluate efficacy and safety of Lu-177-PSMA-617 in a large cohort of patients. Methods: One hundred forty-five patients (median age, 73 y; range, 43-88 y) with mCRPC were treated with Lu-177-PSMA-617 in 12 therapy centers between February 2014 and July 2015 with 1-4 therapy cycles and an activity range of 2-8 GBq per cycle. Toxicity was categorized by the common toxicity criteria for adverse events (version 4.0) on the basis of serial blood tests and the attending physician's report. The primary endpoint for efficacy was biochemical response as defined by a prostate-specific antigen decline 50% from baseline to at least 2 wk after the start of RLT. Results: A total of 248 therapy cycles were performed in 145 patients. Data for biochemical response in 99 patients as well as data for physician-reported and laboratory-based toxicity in 145 and 121 patients, respectively, were available. The median follow-up was 16 wk (range, 2-30 wk). Nineteen patients died during the observation period. Grade 3-4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response. Conclusion: The present retrospective multicenter study of Lu-177-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third-line systemic therapies in mCRPC patients. Future phase II/III studies are warranted to elucidate the survival benefit of this new therapy in patients with mCRPC.

Substantial molecular and clinical heterogeneity of high-grade neuroendocrine neoplasms (NENs) G3, all of which were previously referred to as neuroendocrine carcinomas, has been observed. Although data are still limited, somatostatin receptor expression in well-differentiated G3 NENs of the pancreas (according to the new WHO 2017 classification) may enable peptide receptor radionuclide therapy for these patients. We report our treatment experience of a G3 NEN patient with discordant Ki-67 proliferation indices (between primary tumor and the metastases), who had a long survival over a span of 10 years with excellent quality of life and no adverse effects after repeated cycles of PRRT.

Ectopic Cushing syndrome secondary to corticotropin releasing hormone (CRH)-secreting tumors or CRH and adrenocorticotropin hormone cosecreting tumors is extremely rare. We report here the case of a 54-year-old man who experienced CRH-secreting pancreatic neuroendocrine tumor causing Cushing syndrome, initially detected by SSTR (somatostatin receptor) scintigraphy, then significantly progressed with multiple liver metastases, demonstrating significantly increased SSTR expression on Ga-DOTATOC PET/CT and a "mismatch" imaging pattern on F-FDG PET/CT. The patient underwent peptide receptor radionuclide therapy with Lu/Y-DOTATOC and demonstrated excellent response to the treatment.

BackgroundFor almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: Tb-152 and Tb-155 are the radioisotopes identified for PET or SPECT imaging, while Tb-149 and Tb-161 have suitable decay characteristics for alpha- and combined beta(-)/Auger-e(-)-therapy, respectively. In the present study, the application of Tb-152, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC).Results(152)Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. Tb-152 was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its Lu-177-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, Tb-152 was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25h post injection (p.i.) of the radioligand (140MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by Ga-68-PSMA-11 PET/CT acquired 45min p.i.ConclusionsThe results of this study demonstrate the successful preparation and preclinical testing of Tb-152-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly Tb-161, which has promising decay characteristics for an effective treatment of mCRPC patients.

Patients with metastatic castration-resistant prostate cancer (mCRPC) and visceral (liver or lung) metastases have a poor prognosis and worse outcomes than those with bone disease with or without lymph nodes involvement. The high prostate-specific membrane antigen expression in prostate cancer metastases makes it a promising approach for targeted radionuclide therapy of prostate cancer. Lutetium-177 (Lu)-labeled prostate-specific membrane antigen radioligand therapy (Lu-PRLT) has demonstrated encouraging efficacy in mCRPC. We report here an mCRPC patient with lung, lymph nodes, and extensive bone metastases, who underwent Lu-PRLT and had excellent response to the treatment and complete regression of lung metastases after Lu-PRLT.

Prostate-specific membrane antigen (PSMA) is overexpressed in a majority of prostate cancer cells, which has led to the development of radiolabeled small-molecule inhibitors of PSMA for molecular imaging and targeted radioligand therapy. Lu-labeled PSMA, with therapeutic β-emission and concomitant γ radiation, permits posttherapy imaging for the assessment of biodistribution and uptake in tumors and normal organs, as well as dosimetry. We report a patient with prostate cancer and metastatic lymph nodes-related lower extremity lymphedema, who presented with dermal backflow and soft-tissue uptake in the lower extremity on posttherapeutic whole body scan after intravenous Lu-PSMA treatment.

Aim: The prostate-specific membrane antigen (PSMA) is a cell surface protein, which is overexpressed in nearly all cases of prostate cancer (PCa). PET imaging with 68Ga-PSMA-HBED-CC has recently found widespread application in the diagnosis of recurrent PCa. In this study, the diagnostic potential of 64Cu-labeled PSMA ligand (PSMA-617) PET in patients with PCa has been investigated. Materials and Methods: The study was conducted simultaneously at two nuclear medicine centers, Austria (Vienna, Center 1) and Germany (Bad Berka, Center 2). The patients (n = 29) included in this study were referred for PET (Center 1, 21 patients) or PET/CT (Center 2, 8 patients) imaging with either a high suspicion of recurrent disease or for possible surgical or PSMA radioligand therapy planning. PET images of the whole body were performed at 1 hour p.i. and additional images of the pelvis at 2 hours p.i. Results: In 23 of 29 patients, at least one focus of pathological tracer uptake suspicious for primary disease i...

Background Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany. Methods A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan–Meier curves and uni-variate log rank test Cox models. Findings Median overall survival of all patients was 59 (95% confidence interval [CI] 49–68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83–5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79–5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41–12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18–0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9–46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71–4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2–1.5% of patients. Interpretation These results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events.

The objective of this study was to analyze the safety and efficacy of the 177Lu-labeled DOTAGA-based prostate-specific membrane antigen (PSMA) ligand 177Lu-DOTAGA-(I-y)fk(Sub-KuE) (177Lu-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Fifty-six mCRPC patients underwent PSMA radioligand therapy (RLT) with 177Lu-PSMA. 68Ga-PSMA-(N,N9-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N9-diacetic acid) (68Ga-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:177Lu-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 (68Ga-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 177Lu-PSMA is feasible, safe, and effective in end-stage progressive mCRPC with appropriate selection and follow-up of patients by 68Ga-PSMA PET/CT through application of the concept of theranostics.

Our purpose was to evaluate the safety and efficacy of (68)Ga-DOTATATE PET/CT compared with (111)In-pentetreotide imaging for diagnosis, staging, and restaging of pulmonary and gastroenteropancreatic neuroendocrine tumors.(68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were obtained for 78 of 97 consecutively enrolled patients with known or suspected pulmonary or gastroenteropancreatic neuroendocrine tumors. Safety and toxicity were measured by comparing vital signs, serum chemistry values, or acquisition-related medical complications before and after (68)Ga-DOTATATE injection. Added value was determined by changes in treatment plan when (68)Ga-DOTATATE PET/CT results were added to all prior imaging, including (111)In-pentetreotide. Interobserver reproducibility of (68)Ga-DOTATATE PET/CT scan interpretation was measured between blinded and nonblinded interpreters.(68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were significantly different in impact on treatment (P0.001). (68)Ga-DOTATATE PET/CT combined with CT or liver MRI changed care in 28 of 78 (36%) patients. Interobserver agreement between blinded and nonblinded interpreters was high. No participant had a trial-related event requiring treatment. Mild, transient events were tachycardia in 1, alanine transaminase elevation in 1, and hyperglycemia in 2 participants. No clinically significant arrhythmias occurred. (68)Ga-DOTATATE PET/CT correctly identified 3 patients for peptide-receptor radiotherapy incorrectly classified by (111)In-pentetreotide.(68)Ga-DOTATATE PET/CT was equivalent or superior to (111)In-pentetreotide imaging in all 78 patients. No adverse events requiring treatment were observed. (68)Ga-DOTATATE PET/CT changed treatment in 36% of participants. Given the lack of significant toxicity, lower radiation exposure, and improved accuracy compared with (111)In-pentetreotide, (68)Ga-DOTATATE imaging should be used instead of (111)In-pentetreotide imaging where available.

ZusammenfassungEine Radioligandentherapie (RLT) mit Lutetium-177 markierten Inhibitoren des Prostataspezifischen Membranantigens (177Lu-PSMA) erfolgt bei Patienten mit metastasiertem kastrationsrefraktären Prostatakarzinom (mCRPC) und fehlender Therapiealternative. Die RLT wird an deutschen Universitätsklinika seit 2013 im Rahmen der Ausübung der ärztlichen Heilkunde angeboten. Diese Konsensusempfehlung gibt Orientierung für die Durchführung einer RLT mit 177Lu-PSMA-617. Sie wurde im Rahmen einer Expertenrunde der Deutschen Gesellschaft für Nuklearmedizin (DGN) im Dezember 2015 erarbeitet und enthält Empfehlungen zu Indikationsstellung, Voruntersuchung, Therapieablauf, Begleittherapie, Dosimetrie und Nachsorge. Die Konsensusempfehlung dient der Information des beteiligten medizinischen Personals und zielt auf eine Harmonisierung der Therapieabläufe sowie eine Verbesserung der Qualität der medizinischen Versorgung des einzelnen Patienten.

Radiolabeled somatostatin (SST) analogs, used to visualize and treat SST receptor (SSTR)-expressing neuroendocrine tumors, also accumulate in the spleen. There is a high interpatient variation and no significant radiation-induced splenic toxicity; however, an absorbed dose-related reduction in spleen size was detected. However, the exact localization of radioactivity and the role of SST receptors in splenic retention are unknown. Therefore, we performed ex vivo micro-SPECT of the isolated spleen from a patient with a pancreatic neoplasm after 1 GBq (27 mCi) Lu-DOTATATE administration, followed by autoradiography and immunohistochemistry. Ex vivo autoradiography demonstrated convincingly that most radioactivity accumulated in red pulp.

Purpose Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [Tc-99m]DB1 (Tc-99m-N-4'-DPhe(6),Leu-NHEt13]BBN(6-13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [Ga-68]SB3, a [Tc-99m]DB1 mimic-carrying, instead of the Tc-99m-binding tetraamine, the chelator DOTA for labeling with the PET radiometal Ga-68. Methods Competition binding assays of SB3 and [Ga-nat]SB3 were conducted against [I-125-Tyr(4)]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [Ga-67]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [Ga-67]SB3 (37 kBq, 100 mu L, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [Ga-68]SB3 (283 +/- 91 MBq, 23 +/- 7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60-115 min pi. Results SB3 and [Ga-nat]SB3 bound to the human GRPR with high affinity (IC50: 4.6 +/- 0.5 nM and 1.5 +/- 0.3 nM, respectively). [Ga-67]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [Ga-67]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1 +/- 3.9%ID/g at 1 h pi - 27.0 +/- 0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (a parts per thousand 160%ID/g at 1 h pi to

3568 Background: Peptide receptor radionuclide therapy (PRRT) is an effective therapy for metastatic/inoperable neuroendocrine tumors (NETs). Tools to predict and monitor the efficacy of therapy are important adjuncts in the radio-oncology armamentarium. Standard blood biomarkers are not effective by new molecular based assays such as the PRRT Predictive Quotient (PPQ) and NETest are effective as real-time predictors and monitors of therapy. We aimed to prospectively evaluate whether: 1) the NETest functioned as a surrogate biomarker for image-based per RECIST evaluation of PRRT efficacy; 2) there was a correlation between changes in NETest levels during therapy, PPQ prediction and treatment efficacy. Methods: Three independent 177Lu-PRRT-treated GEP-NET and BPNEN cohorts (Rotterdam, Netherlands: n= 41; Bad-Berka, Germany: n= 44; Meldola, Italy: n= 72). Treatment response: RECIST1.1 [Responder (stable, partial/complete response) vs Non-Responder]. Blood sampling: pre-PRRT, prior to each cycle and 6 months (median) after completion of all cycles. PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable 40). CgA (ELISA) as comparator. Samples deidentified, measurement and analyses blinded. Kaplan-Meier survival and Mann-Whitney analyses. Results: 122 of 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly ( p< 0.0001) decreased in RECIST-“responders” (-47±3%); in “non-responders” it elevated (+79±19%, p< 0.0005). NETest monitoring accuracy 98% (119/122). Follow-up levels > 40 (progressive) vs stable ( 97%) with the pretreatment PPQ response predictor.

625 Background: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is most effective after treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy, NETest monitors disease. We prospectively evaluated: 1) NETest as a surrogate biomarker for RECIST; 2) Correlation of NETest levels, PPQ prediction and treatment efficacy. Methods: Three independent 177Lu-PRRT-treated GEP-NET and BPNEN cohorts (Rotterdam, Netherlands: n=41; Bad-Berka, Germany: n=44; Meldola, Italy: n=72). Treatment response: RECIST1.1 [Responder (stable, partial/complete response) vs Non-Responder]. Blood sampling: pre-PRRT, prior to each cycle and 6 months (median) after completion of all cycles. PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable40). CgA (ELISA) as comparator. Samples deidentified, measurement and analyses blinded. Kaplan-Meier survival and Mann-Whitney analyses. Results: 122 of 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly ( p40 (progressive) vs stable (97%) with the pretreatment PPQ response predictor.

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 (99m)Tc and (111)In or positron emitters like (68)Ga and (18)F for diagnosis as well as with their theranostic pairs such as (177)Lu (β-emitter) or (225)Ac (α-emitter) for therapy. This review summarizes the theranostic role of PSMA ligands for molecular imaging and targeted molecular radiotherapy, moving towards precision oncology.

Since the first clinical use of 131I-labeled prostate-specific membrane antigen (PSMA) ([1][1]), xerostomia has been identified as a relevant side effect of PSMA radioligand therapies (PRLTs) for metastatic castration-resistant prostate cancer. Given the remarkable progress when using 177Lu-labeled

Introduction The Prostate Cancer Foundation (PCF) convened a PSMA-Directed Radionuclide Scientific Working Group on November 14, 2017, at Weill Cornell Medicine, New York, NY. Methods The meeting was attended by 35 global investigators with expertise in prostate cancer biology, radionuclide therapy, molecular imaging, prostate-specific membrane antigen (PSMA)-targeted agents, drug development, and prostate cancer clinical trials. The goal of this meeting was to discuss the potential for using PSMA-targeted radionuclide agents for the treatment of advanced prostate cancer and to define the studies and clinical trials necessary for validating and optimizing the use of these agents. Results Several major topic areas were discussed including the overview of PSMA biology, lessons and applications of PSMA-targeted PET imaging, the nuances of designing PSMA-targeted radionuclide agents, clinical experiences with PSMA-targeted radionuclides, PCF-funded projects to accelerate PSMA-targeted radionuclide therapy, and barriers to the use of radionuclide treatments in widespread clinical practice. Discussion This article reviews the major topics discussed at the meeting with the goal of promoting research that will validate and optimize the use of PSMA-targeted radionuclide therapies for the treatment of advanced prostate cancer.

Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT “responders” from “non-responders”. This study clinically validates the utility of the PPQ in NETs. The development and validation of the PPQ was undertaken in three independent 177Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n = 44), and Erasmus Medical Center, Rotterdam, Netherlands (n = 42). Each cohort included predominantly well differentiated, low grade (86–95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: “predicted responder” (PPQ+); “predicted non-responder” (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses. In the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64–79%), the PPQ was 95% accurate (Bad Berka: PPQ + =97%, PPQ- = 93%; Rotterdam: PPQ + =94%, PPQ- = 100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10–14 months; HR: 18–77, p