Molecular radiotheranostics for neuroendocrine tumours

This article discusses the important role of nuclear medicine imaging and therapy in the management of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy has a high impact on patient management versus conventional imaging. Molecular radiotherapy is an important part of the management of patients with NETs. Selection of patients for molecular radiotherapy in NETs is based on uptake on their radionuclide imaging study. The imaging agent has the same mechanism of uptake as the therapeutic agent. Thus, the imaging study preselects patients that are likely to concentrate radiation within their tumours

Safety, tolerability and clinical implementation of 'ready-to-use' 68gallium-DOTA0-Tyr3-octreotide (68Ga-DOTATOC) (SomaKIT TOC) for injection in patients diagnosed with gastroenteropancreatic neuroendocrine tumours (GEP-NETs)

BACKGROUND: 68Ga-DOTA0-Tyr3-octreotide (68Ga-DOTATOC) positron emission tomography-CT (PET-CT) has superior diagnostic performance compared to the licensed tracer OctreoScan single photon emission CT-CT in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs). A new preparation of 68Ga-DOTATOC using a new 'ready-to-use' 68Ga-DOTATOC formulation for injection has been developed (68Ga-DOTATOC (SomaKIT TOC)). OBJECTIVES: This study aimed to assess the safety and tolerability of 68Ga-DOTATOC (SomaKIT TOC) and evaluate the feasibility and robustness of implementing it in a NET clinical imaging service. METHODS: A first-in-human phase I/II multicentre, open-label study of a single dose of 68Ga-DOTATOC (SomaKIT TOC) 2 MBq/kg±10% (range 100-200 MBq) in patients with biopsy-proven grade 1-2 GEP-NETs. PET-CT was performed post injection. Patients were followed up for 28 days. We next implemented this new synthesis methodology in a clinical service assessed over 11 months. RESULTS: Twenty consenting patients were recruited; 14 males, 6 females; mean (SD) age 58 years (12); NET grade 1 (70%), grade 2 (30%); and 75% with stage IV disease. Twelve patients experienced at least one adverse event (AE) during the study with no grade 3-4 toxicities. Only four AEs were classified as possibly (headache (n=1; 4%), nausea (1; 4%)) or probably (dysgeusia (1; 4%), paraesthesia (1; 4%)) related to the study preparation. One hundred thirteen vials of 68Ga-DOTATOC (SomaKIT TOC) were synthesised with the 'kit' over a period of 11 months for clinical utility. Only 2/113 vials (1.77%) were rejected. CONCLUSIONS: The new ready-to-use preparation of 68Ga-DOTATOC (SomaKIT TOC) for injection was safe and well tolerated. This has led to the world's first (EMA) licensed 68Ga-DOTATOC (SomaKIT TOC) radiopharmaceutical for the utility of PET imaging in patients with NETs. This preparation can be robustly implemented into routine clinical practice

Understanding the Treatment Algorithm of Patients with Metastatic Pancreatic Neuroendocrine Neoplasms: A Single-Institution Retrospective Analysis Comparing Outcomes of Chemotherapy, Molecular Targeted Therapy, and Peptide Receptor Radionuclide Therapy in 255 Patients

Background The number of therapeutic options for patients with pancreatic neuroendocrine neoplasms (PNEN) has increased, but the optimal therapeutic algorithm has not been defined due to lack of randomised trials comparing different modalities. Methods We performed a retrospective study in patients with metastatic PNEN treated with ≥1 line of systemic therapy. The relationship between baseline characteristics, treatment type and time to treatment failure (TTF), time to progression (TTP) and overall survival (OS) was analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. Results Two hundred and fifty-five patients with metastatic PNEN had 491 evaluable lines of therapy. Independent predictors of TTF included treatment type, Ki-67, tumour grade and chromogranin A. To reduce selection bias, a subgroup of 114 patients with grade 2 (G2) metastatic pancreatic neuroendocrine tumours (PNET) was analysed separately. These patients had received 234 lines of treatment (105 chemotherapy, 82 molecular targeted therapy, and 47 peptide receptor radionuclide therapy [PRRT]). In the G2 cohort, TTF and TTP were superior for PRRT compared with both chemotherapy and molecular targeted therapy. OS in the G2 cohort was also superior for those that had received PRRT compared with those that had not (median 84 vs 56 months; HR 0.55, 95%CI 0.31-0.98, p=0.04). Conclusions This study suggests that PRRT is associated with superior clinical outcomes relative to other systemic therapies for G2 metastatic PNET. Prospective studies are required to confirm these observations

Predictors of antiproliferative effect of lanreotide autogel in advanced gastroenteropancreatic neuroendocrine neoplasms

PURPOSE: The antiproliferative properties of lanreotide autogel (LAN) in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) were demonstrated in the CLARINET study. However, there is limited literature regarding factors that affect progression-free survival (PFS) in patients with GEP NENs treated with LAN. METHODS: We identified a total of 191 treatment-naive patients with advanced GEP NENs and positive SSTR uptake on imaging (Octreoscan or 68Gallium DOTATATE Positron Emission Tomography [68GaPET]) who received first-line LAN monotherapy, albeit at various starting doses (60, 90 or 120 mg/month). A group of 102 patients who initiated treatment at the standard dose of 120 mg/month were included in the study and further evaluated by univariate and multivariate analyses to identify predictors of PFS. RESULTS: The location of tumour primary was in the small bowel in 63 (62%), pancreas in 31 (30%) and colon/rectum in 8 patients (8%). The tumours were well-differentiated, and the majority were grade 1 (52%), or 2 (38%). About 60% of cases had progressive disease at the time of treatment initiation. Most patients with available pretreatment nuclear medicine imaging (Octreoscan or 68Ga PET) had a Krenning score of 3 (44%) or 4 (50%). The median PFS for the entire cohort was 19 months (95% CI 12, 26 months). The univariate analysis demonstrated that grade 2 tumours, progressive disease at baseline and metastatic liver disease were associated with a significantly shorter PFS, while other evaluated variables did not affect PFS at a statistically significant level. However, at multivariate analysis only the tumour grade remained statistically significant. CONCLUSIONS: The current study showed that, of many evaluated variables, only the tumour grade was predictive of PFS duration and this should be considered during patient selection for treatment

111In-DTPA-Octreotide SPECT (OctreoScan) uptake in metastatic renal cell carcinoma to the pancreas

We report a case of late presentation of metastatic renal cell carcinoma (RCC) demonstrating intense 111In-DTPA-octreotide uptake in pancreas without recurrence at the primary site. Immunohistochemistry study revealed somatostatin receptor subtype 2 of metastatic RCC preferentially expressed on tumor endothelial cells. The typical hypervascular features of RCC with intense homogeneous contrast enhancement in the arterial phase on CT should raise the possibility of metastatic RCC. This case illustrates that RCC can demonstrate high octreotide uptake in abdominal metastases

111In-DTPA-Octreotide SPECT (OctreoScan) uptake in metastatic renal cell carcinoma to the pancreas

We report a case of late presentation of metastatic renal cell carcinoma (RCC) demonstrating intense 111In-DTPA-octreotide uptake in pancreas without recurrence at the primary site. Immunohistochemistry study revealed somatostatin receptor subtype 2 of metastatic RCC preferentially expressed on tumor endothelial cells. The typical hypervascular features of RCC with intense homogeneous contrast enhancement in the arterial phase on CT should raise the possibility of metastatic RCC. This case illustrates that RCC can demonstrate high octreotide uptake in abdominal metastases

A case series of outcomes in isolated subsegmental pulmonary embolism on ventilation–perfusion imaging

OBJECTIVES: The risk of recurrent venous thromboembolic disease and the management of patients with isolated subsegmental pulmonary embolism (SSPE) remain unclear. We sought to assess the long-term clinical outcome of patients with isolated SSPE demonstrated by isolated subsegmental mismatch found on ventilation/perfusion (V/Q) scans. PATIENTS AND METHODS: We performed a retrospective observational study of 1300 consecutive patients with suspected pulmonary embolism who underwent index V/Q single-photon emission computed tomography between 2012 and 2013. Forty (3%) patients were found to have isolated SSPE identified on V/Q scan. Of the 40 patients with isolated SSPE on V/Q scan, 19 underwent further investigation with computed tomography pulmonary angiogram (CTPA) within 48 h. RESULTS: Among 19 patients who had corroborating CTPA performed concurrently, 94.7% of the SSPEs identified on V/Q were not detectable on CTPA. Of the 40 patients, 10 (25%) were anticoagulated. In a median follow-up of 3.28±0.55 years, all-cause mortality occurred in two patients, recurrence of suspected venous thromboembolism (VTE) occurred in 12 (30%) of 40 patients, but none had confirmed recurrent thromboembolism on further imaging. In the 40 patients with SSPE on V/Q, there was no difference in the risk of recurrence of suspected VTE or mortality between patients treated with anticoagulation and not treated (hazard ratio: 2.04, 95% confidence interval: 0.75-7.28). CONCLUSION: In this case series, a large proportion of patients with isolated SSPE on V/Q imaging were not identified on corroborating CTPA performed within 48 h. In patients with isolated SSPE (identified by isolated subsegmental mismatch on V/Q single-photon emission computed tomography), we found no difference in risk of recurrent suspected VTE or all-cause mortality in those treated with anticoagulation and those not treated

Peptide Receptor Radionuclide Treatment and (131)I-MIBG in the management of patients with metastatic/progressive phaeochromocytomas and paragangliomas

BACKGROUND AND OBJECTIVES: Radionuclide therapy has been used to treat patients with progressive/metastatic paragangliomas (PGLs) and phaeochromocytomas (PCCs). The aim of the present study is to retrospectively compare the therapeutic outcomes of these modalities in patients with progressive/metastatic PCCs and PGLs. METHODS: Patients with progressive/metastatic PGLs and PCCs that were subjected to radionuclide treatment in our department were retrieved from our department&apos;s database for the period 1998-2013. Overall survival (OS), progression free survival (PFS), event free survival (EFS), and response to treatment were calculated. Treatment toxicity was documented. RESULTS: Twenty-two patients with progressive/metastatic PGLs or PCCs were treated with either (131)I-MIBG, (90)Y-DOTATATE or (177)Lu-DOTATATE. A total of 30 treatments were administered (16 treatments with (131)I-MIBG, 2 with (177)Lu-DOTATATE, and 12 with (90)Y-DOTATATE. Patients treated with PRRT had increased PFS and response to treatment compared to (131)I-MIBG treated patients (P<0.05). However, difference in OS was non significant (P=0.09). There was no difference in major toxicities between groups. When comparing only patients with PGLs, OS, PFS, EFS, and response to treatment were significantly higher in the PRRT treatment group. CONCLUSION: PRRT treatment offers increased OS, PFS, EFS, and response to treatment compared to (131)I-MIBG therapy in patients with progressive/malignant PGLs

Peptide Receptor Radionuclide Treatment and (131)I-MIBG in the management of patients with metastatic/progressive phaeochromocytomas and paragangliomas

BACKGROUND AND OBJECTIVES: Radionuclide therapy has been used to treat patients with progressive/metastatic paragangliomas (PGLs) and phaeochromocytomas (PCCs). The aim of the present study is to retrospectively compare the therapeutic outcomes of these modalities in patients with progressive/metastatic PCCs and PGLs. METHODS: Patients with progressive/metastatic PGLs and PCCs that were subjected to radionuclide treatment in our department were retrieved from our department&amp;apos;s database for the period 1998-2013. Overall survival (OS), progression free survival (PFS), event free survival (EFS), and response to treatment were calculated. Treatment toxicity was documented. RESULTS: Twenty-two patients with progressive/metastatic PGLs or PCCs were treated with either (131)I-MIBG, (90)Y-DOTATATE or (177)Lu-DOTATATE. A total of 30 treatments were administered (16 treatments with (131)I-MIBG, 2 with (177)Lu-DOTATATE, and 12 with (90)Y-DOTATATE. Patients treated with PRRT had increased PFS and response to treatment compared to (131)I-MIBG treated patients (P&lt;0.05). However, difference in OS was non significant (P=0.09). There was no difference in major toxicities between groups. When comparing only patients with PGLs, OS, PFS, EFS, and response to treatment were significantly higher in the PRRT treatment group. CONCLUSION: PRRT treatment offers increased OS, PFS, EFS, and response to treatment compared to (131)I-MIBG therapy in patients with progressive/malignant PGLs.</p