Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11

A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood

Background: The lack of an accurate blood biomarker in neuroendocrine tumor (NET) disease has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy—liquid biopsy—to facilitate real-time management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD). Patients and methods: A systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified ten original scientific papers that met the inclusion criteria. These were assessed by qualitative analysis and thereafter meta-analysis. Data were pooled and a median [95% confidence interval (CI)] diagnostic odds ratio (DOR), positive likelihood ratio (+LR), and negative likelihood ratio (−LR) were calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and area under the curve (AUC) data. Results: The ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. The meta-analysis identified the diagnostic accuracy of the NETest to be 95%–96% with a mean DOR of 5 853, +LR of 195, and −LR of 0.06. The NETest was 84.5%–85.5% accurate in differentiating stable disease from progressive disease. As a marker of natural history, the accuracy was 91.5%–97.8%. As an interventional/response biomarker, the accuracy was 93.7%–97.4%. The pooled AUC for the NETest was 0.954 ± 0.005, with a z-statistic of 175.06 (P < 0.001). Conclusions: The NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of this as a biomarker provides information relevant to NET management consistent with observations regarding utility of liquid biopsies in other oncological disciplines. © 2019 European Society for Medical Oncolog

Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors

Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1, 2, 3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotideLAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary end points in cluded over all survival (OS), over all radiographic responserate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-monthOSrate was 70%. The best radiographic response was partial response inone patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response

Temozolomide in Advanced Neuroendocrine Neoplasms: Pharmacological and Clinical Aspects

Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first-line treatment. Although in NENs, determination of the O6-methylguanine-DNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response. © 2015 S. Karger AG, Basel

Supplementary Material for: Follow-Up for Resected Gastroenteropancreatic Neuroendocrine Tumours: A Practice Survey of the Commonwealth Neuroendocrine Tumour Collaboration (CommNETS) and the North American Neuroendocrine Tumor Society (NANETS)

<b><i>Objectives:</i></b> There is no consensus regarding optimal follow-up in resected gastroenteropancreatic neuroendocrine tumours (NETs). We aimed to perform a practice survey to ascertain follow-up patterns by health care practitioners and highlight areas of variation that may benefit from further quantitative research. <b><i>Methods:</i></b> A Web-based survey targeted at NET health care providers in Australia, New Zealand, Canada, and the USA was developed by a steering committee of medical oncologists and a research methodologist. Thirty-seven questions elicited information regarding adherence to guidelines, the influence of risk factors on follow-up, and the frequency and choice of modality in follow-up. <b><i>Results:</i></b> There were 163 respondents: 59 from Australia, 25 from New Zealand, 46 from Canada, and 33 from the USA (50% medical oncology, 23% surgery, 13% nuclear medicine, and 15% other). Thirty-eight percent of the respondents were “very familiar” with the NCCN NET guidelines, 33% with the ENETS guidelines, and 17% with the ESMO guidelines; however, only 15, 27, and 10%, respectively, found them “very useful”; 63% reported not using guidelines at their institution. The commonest investigations used were CT scans (66%) and chromogranin A (86%). The US respondents were more likely to follow patients up past 5 years, and the Australian respondents utilized more functional and less cross-sectional imaging. When poor prognostic factors were introduced, the respondents recommended more visits and tests. <b><i>Conclusions:</i></b> This large international survey highlights variation in current follow-up practices not well addressed by the current guidelines. More quantitative research is required to inform the development of evidence-based guidelines tailored to the pattern of recurrence in NETs

A phase II study of axitinib in advanced neuroendocrine tumors

Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing vascular endothelial growth factor (VEGF) as well as VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment of advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial of axitinib 5 mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were progression-free survival (PFS) and 12-month PFS rate. The secondary end points included time to treatment failure (TTF), overall survival (OS), overall radiographic response rate (ORR), biochemical response rate and safety. A total of 30 patients were enrolled and assessable for toxicity; 22 patients were assessable for response. After a median follow-up of 29 months, we observed a median PFS of 26.7 months (95% CI, 11.4-35.1), with a 12-month PFS rate of 74.5% (±10.2). The median OS was 45.3 months (95% CI, 24.4-45.3), and the median TTF was 9.6 months (95% CI, 5.5-12). The best radiographic response was partial response (PR) in 1/30 (3%) and stable disease (SD) in 21/30 patients (70%); 8/30 patients (27%) were unevaluable due to early withdrawal due to toxicity. Hypertension was the most common toxicity that developed in 27 patients (90%). Grade 3/4 hypertension was recorded in 19 patients (63%), leading to treatment discontinuation in six patients (20%). Although axitinib appears to have an inhibitory effect on tumor growth in patients with advanced, progressive carcinoid tumors, the high rate of grade 3/4 hypertension may represent a potential impediment to its use in unselected patients

Metastatic type 1 gastric carcinoid: A real threat or just a myth?

AIM: To describe disease characteristics and treatment modalities in a group of rare patients with metastatic gastric carcinoid type 1 (GCA1). METHODS: Information on clinical, biochemical, radiological, histopathological findings, the extent of the disease, as well as the use of different therapeutic modalities and the long-term outcome were recorded. Patients&apos; data were assessed at presentation, and thereafter at 6 to 12 monthly intervals both clinically and biochemically, but also endoscopically and histopathologically. Patients were evaluated for the presence of specific symptoms; the presence of autoimmune disorders and the presence of other gastrointestinal malignancies in other family members were also recorded. The evaluation of response to treatment was defined using established WHO criteria. RESULTS: We studied twenty consecutive patients with a mean age of 55.1 years. The mean follow-up period was 83 mo. Twelve patients had regional lymph node metastases and 8 patients had liver metastases. The primary tumor mean diameter was 20.13 ± 10.83 mm (mean ± SD). The mean Ki-67 index was 6.8% ± 11.2%. All but one patient underwent endoscopic or surgical excision of the tumor. The disease was stable in all but 3 patients who had progressive liver disease. All patients remained alive during the follow-up period. CONCLUSION: Metastatic GCA1 carries a good overall prognosis, being related to a tumor size of ≥ 1 cm, an elevated Ki-67 index and high serum gastrin levels. © 2013 Baishideng Publishing Group Co., Limited. All rights reserved