Paragangliomas and pheochromytomas (PPGLs) exhibit variable malignancy, advanced/hormonally active/progressive need therapy. PRRT (Peptide Receptor Radionuclide Therapy) could be an option for these patients. To evaluate the effectiveness of PRRT (90Y DOTATATE), based on overall survival (OS) and progression-free survival (PFS), in patients with PPGLs, related to SDHx gene mutation, we conducted a prospective open-label, single-center, phase II study. Thirteen patients were observed, eight PGL1 and five PGL4, all with advanced, non-resectable tumors, and eight had metastases. All were treated with 90Y DOTATATE. Efficacy was based on OS and PFS, and radiological response was based on RECIST. Hormonal activity was evaluated using serum-fractionated free catecholamines. Eight subjects had a clinical response, three were stable, and two exhibited disease progression. Among four patients with hormonally-active PPGLs, three showed a reduction and one showed normalization. OS for all was 68.0 months; PFS was 35.0 months. OS in PGL4 = 25.0 vs. N.R. (not reached) in PGL1. PFS in PGL4 = 12.0 vs. N.R. in PGL1. A difference was seen in the OS and PFS in patients who did not respond clinically, compared to those who did, OS = 22.0 vs. N.R. PFS = 7.0 vs. N.R. A difference in the OS and PFS was noted in patients with liver and bone involvement compared to those without. PRRT is an effective therapy in selected population of patients with SDHx, in those with locally-advanced, non-resectable tumors. Furthermore, it is effective regardless of the secretory status.

Peptide Receptor Radionuclide Therapy (PRRT) is a form of molecular targeted therapy which is performed by using a small peptide (somatostatin analogue - SSA) that is coupled with a radionuclide beta emitting radiation. PRRT is a nuclear medicine for the systemic treatment of non-resectable, metastasized well/moderately differentiated, neuroendocrine tumours (NET) with overexpression of somatostatin receptor. These types of tumours include gastroenteropancreatic neoplasm (GEP-NENs), e.g. arising from the small bowel (often called carcinoid tumours), the pancreas, duodenum or stomach, but also from the large bowel or the lung and many other tissues (so called diffuse neuroendocrine system). The goal of PRRT is irradiation of tumour cells, via direct binding into specific receptor, somatostatin receptors (SSTR) family, overexpressed on the cell membrane of the primary tumours as well as on the metastasis. Over many years of clinical use of PRRT with Y-90 and current with Lu-177 DOTA conjugated somatostatin analogues proved to be efficient therapy option for NETs, with tumour responses, base on radiological evaluation. Also, a clinical response with symptoms relief and improvement in quality of life based on standard EORTC questioners is seen. Additional, common NET biomarker reduction and, ultimately, an impact on overall survival (OS) of patients with advanced non-resectable often progressive NEN can be expected. PRRT with Y-90 or Lu-177-labelled peptides is generally well tolerated by most of the patients. The acute side effects (Adverse Events - AEs) are usually mild; most of them are related to the co-administration of amino acids (AA), such as nausea and vomiting. Others are related to the radioisotopes, such as fatigue or the exacerbation of endocrine syndromes, which are very rarely and they occurs, only in patients with functional tumours and large tumours burden. Chronic and permanent damage has an effect on target organs, particularly the kidneys and the bone marrow, which are generally mild. Currently, when Lu-177 DOTATATE is used, the potential risk to kidney damage is significantly reduced, compared to the previous usage of Y-90 labelled analogues. Up to now, kidney and bone marrow toxicity limits the dose of radioactivity of PRRT.

Background and Objectives: Large cell neuroendocrine cancer is characterised by poor prognosis. The standard of treatment is still not established. The aim of this study was to assess the predictive factors of overall survival (OS) and progression-free survival (PFS) of pulmonary large cell neuroendocrine carcinoma (LCNEC) and combined LCNEC. Materials and Methods: All patients had confirmed pathology stage I-IV disease recorded between period 2002–2018. Survival curves were estimated by Kaplan–Meier method. Uni- and multivariable analysis was conducted using Cox-regression analysis. Results: A total of 132 patients with LCNEC and combined LCNEC were included. Half of them had clinical stage IIIB/C-IV. Patients were treated with radical (n = 67, including surgery alone; resection with neo-adjuvant or adjuvant chemotherapy, radiochemotherapy, or adjuvant radiotherapy; patients treated with radiochemotherapy alone), palliative (n = 41) or symptomatic (n = 24) intention. Seventeen patients were treated with resection margin R1 or R2. Non-small cell carcinoma (NSCLC) chemotherapy (platinum-vinorelbine; PN schedule) and small-cell lung carcinoma (SCLC) chemotherapy approaches (platinum/carboplatinum-etoposide; PE/KE schedule) were administered in 20 and in 55 patients, respectively. The median (95% Confidence Interval (CI)) OS and PFS were 17 months (9.0–36.2 months) and 7 months (3.0–15.0 months), respectively. Patients treated with negative resection margin, with lower clinical stage, without lymph node metastasis, and with size of primary tumour ≤4 cm showed significantly better OS and PFS. The main risk factors with an adverse effect on survival were advanced CS and positive resection margin. Conclusions: Patients with LCNEC characterized poor prognosis. Independent prognostic factors influencing PFS were initial clinical stage and resection margin R0 vs. R1-2.

This study was performed to determine if intra-arterial (i.a.) administration of ⁹⁰Y DOTATATE can provide an effective and safe alternative to the accepted standard for i.v. of peptide receptor radionuclide therapy (PRRT) in liver-dominant metastases of gastrointestinal pancreatic neuroendocrine neoplasm (GEP-NEN). A single site, prospective, preliminary case series study included 39 patients with histologically proven liver-dominant NEN. PRRT in the form of 1.15GBq ⁹⁰Y DOTATATE was given selectively into the liver via radiological catheterization of the hepatic artery, up to four times. The endpoint was radiological response (RECIST). Secondary endpoints assessed clinical well-being post-treatment, progression-free survival (PFS), overall survival (OS), and toxicity. Partial response (PR) was noted in 13% of subjects six weeks post-therapy, increasing to 24% at six months and dropping to 13% at 36 months. Disease progression (DP) was not seen at six weeks, was 5% at six months, and 47% at 36 months. Clinical response based on PS seen in 74% of patients at six weeks, 69% at six months, and 39% at 36 months had PFS and OS, respectively, of 22.7 months and 38.2 months. There was no difference in OS/PFS between those with RECIST PR and SD. One patient had significant toxicity (3%). Use of i.a. PRRT appears to be safe and effective in treating patients with liver-dominant NEN. In addition, the best OS (51 vs. 22 months) was seen when i.a. was used as an upfront treatment of bulky GEP-NEN liver metastases and not after i.v. ⁹⁰Y DOTATATE. The use of i.a. ⁹⁰Y DOTATATE PRRT appears to be safe and effective in treating patients with liver-dominant NEN.

Large-cell neuroendocrine carcinoma (LCNEC) is a rare malignancy with poor prognosis. The rationale of the study was to determine the survival of LCNEC patients in I–IIIA clinical stages who underwent resection. A total of 53 LCNEC (89%) and combined LCNEC (11%) patients in stages I–IIIA who underwent surgery with radical intent between 2002–2018 were included in the current study. Overall survival (OS) and time to recurrence (TTR) were estimated. Uni- and multivariable analyses were conducted using Cox-regression model. Patients were treated with surgery alone (51%), surgery with radiochemotherapy (4%), with radiotherapy (2%), with adjuvant chemotherapy (41%), or with neoadjuvant chemotherapy (2%). The median (95% Confidence Interval (CI)) OS and TTR was 52 months (20.1–102.1 months) and 20 months (7.0–75.6 months), respectively. Patients treated in clinical stage I showed better OS than patients in stages II–IIIA (p = 0.008). Patients with R0 resection margin (negative margin, no tumor at the margin) and without lymph node metastasis had significantly better TTR. In the multivariate analysis, age was an independent factor influencing OS. Recurrence within 1 year was noted in more than half cases of LCNEC. R0 resection margin and N0 status (no lymph node metastasis) were factors improving TTR. Age >64 years was observed as a main independent factor influencing OS.

BACKGROUND: Neuroendocrine neoplasms of the pancreas (p-NEN) are common gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). The aim of this retrospective study was to review the value of Somatostatin Receptor Scintigraphy (SRS) in initial detection of p-NEN, evaluation of tumour extent and as imaging follow-up after radical surgery in patients with confirmed well (NETG1) or moderately (NETG2) differentiated p-NEN based on pathological WHO 2017 classification. MATERIAL AND METHODS: Overall 281 patients with confirmed p-NEN were enrolled. The SRS was performed to evaluate primary p-NEN, to assess clinical stage of disease, based on current World Health Organization (WHO) classification and during clinical follow-up. A total of 829 examinations were performed over time in these 281 patients using Tc-99m HYNICTOC. Images were acquired between 1-3 h after i.v. injection of radiotracer. Initially whole body WB-SPECT and then WB-SPECT/CT with standard iterative reconstruction were used. RESULTS: There were 159 patients with NETG1 (57%) and 122 subjects with NETG2 (43%). The female to male ratio was 1.1:1. In 68 patients (22%) with NETG1/G2 eighty-seven SRSs (10%) were performed to confirm initial diagnosis. SRS results were as follow: true positive (TP) = 84 (97%), false negative (FN) = 3 (3%), no true negative (TN) or false positive (FP) results of SRS examination (sensitivity of SRS per patient was 96%). In 198 subjects (66%) SRS was used in evaluation and re-evaluation of the clinical stage. A total of 661 (80%) examinations were carried out in these patients. There were TP = 514 (77%), TN = 136 (21%), FN = 7 (1%) and FP = 4 (1%) results. The sensitivity and specificity per patient were: 96% and 95%. The sensitivity and specificity per study were: 98% and 97%. In 35 patients (12%) SRS was used as imaging follow-up after radical surgery; there were overall 81 examinations (10%) performed. There were 76 (91%) TN results of SRS examinations and in 4 patients we identified recurrence (TP). In total, which consists of initial diagnosis/staging and patient follow-up, the sensitivity of SRS was 96% and specificity 97% per patient and per study sensitivity and specificity was 98%. CONCLUSIONS: SRS using Tc-99m HYNICTOC acquired in WB-SPECT or WB-SPECT/CT techniques is an excellent imaging modality in detection of primary NETG1/G2 p-NEN. Our study confirms that SRS has high sensitivity and specificity, as a result has tremendous value as an examination method to assess clinical stage of disease and as an imaging follow-up after radical treatment.