Effect of Endostar combined with chemotherapy in advanced well-differentiated pancreatic neuroendocrine tumors.
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ABSTRACT:
SUBMITTER: Cheng YJ
PROVIDER: S-EPMC6250533 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
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Effect of Endostar combined with chemotherapy in advanced well-differentiated pancreatic neuroendocrine tumors.
Cheng Yue-Juan YJ Meng Chang-Ting CT Ying Hong-Yan HY Zhou Jian-Feng JF Yan Xiao-Yan XY Gao Xin X Zhou Na N Bai Chun-Mei CM
Medicine 20181101 45
The aim of the present study was to assess the effect of Endostar and temozolomide or dacarbazine plus 5-fluorouracil (5-FU) in patients with advanced pancreatic neuroendocrine tumors (pNETs).Phase II study of 14 patients with locally advanced or metastatic well-differentiated pNETs treated between April 2013 and September 2016. Patients received temozolomide or dacarbazine plus 5-FU, and Endostar. The primary outcome was the radiographic response rate.All 14 patients had nonfunctional pNETs. Si ...[more]
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Project description:Treatments for advanced neuroendocrine tumors were, until recently, rather limited. Salvage surgery and liver-directed therapy both have relatively limited impact, and systemic cytotoxic chemotherapy has minimal efficacy. In the absence of other effective treatments, somatostatin analogs have been used for years to control disease and neuroendocrine symptoms, without cytotoxic intent. Advances in targeted therapy for neuroendocrine tumors have opened several potentially new treatment paradigms in the management of these otherwise relatively drug-resistant neoplasms. Promising results have emerged from studies evaluating radiolabeled somatostatin analogs and inhibitors of the vascular endothelial growth factor and mammalian target of rapamycin pathways. This article reviews several of the more encouraging developments in this field.
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Project description:BackgroundNeuroendocrine tumors (NETs) are believed to be relatively rare and to follow a generally indolent course. However, liver metastases are common in NET patients and the outcome of NET liver metastasis is poor. In Western countries, streptozocin (STZ) has been established as a first-line anticancer drug for unresectable NET; however, STZ cannot be used in daily practice in Japan. The aim of the present study was to determine the status of STZ usage in Japan and to evaluate the effectiveness and safety of STZ chemotherapy in Japanese NET patients.MethodsA retrospective multi-center survey was conducted. Five institutions with experience performing STZ chemotherapy participated in the study. The patient demographics, tumor characteristics, context of STZ chemotherapy, and patient outcome were collected and assessed.ResultsFifty-four patients were enrolled. The main recipients of STZ chemotherapy were middle-aged patients with pancreatic NET and unresectable liver metastases. The predominant regimen was the weekly/bi-weekly intravenous administration of STZ combined with other oral anticancer agents. STZ monotherapy was used in one-fourth of the patients. The median progression-free and overall survival periods were 11.8 and 38.7 months, respectively, and sustained stable disease was obtained in some selected patients. The adverse events profile was mild and tolerable.ConclusionsOur survey showed the clinical benefit and safety of STZ therapy for Japanese patients with unresectable NET. Therefore, we recommend that STZ, which is the only cytotoxic agent available against NET, should be used in daily practice in Japan.
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Project description:Neuroendocrine tumors (NETs) comprise a group of rare tumors derived from the diffuse neuroendocrine system or islet endocrine cells of the pancreas. The molecular mechanisms underlying NETs are largely unknown. The tumor suppressor p53 plays a critical role in maintaining genomic stability and tumor prevention. The p53 pathway is tightly regulated by a number of proteins, among which MDM2, MDM4, and WIP1 are key negative regulators of p53 protein levels or activity. Aberrant activation of these negative regulators can attenuate the p53 function that serves as an important mechanism of tumorigenesis. In this study, several genetic alterations in pancreatic NETs were studied. These tumors exhibit various chromosomal aberrations throughout the whole genome as examined by array-based comparative genomic hybridization. Although p53 mutations are rare in NETs (<3%), this study presents evidence that the p53 pathway is altered in pancreatic NETs through aberrant activation of its negative regulators. A high percentage of pancreatic NETs contain extra gene copies of MDM2 (22%), MDM4 (30%), and WIP1 (51%), which are correlated with expression of corresponding mRNAs and proteins. In addition, there is a higher frequency (23% v. 15% in the control population) of the G/G genotype of MDM2 SNP309, a functional single-nucleotide polymorphism in the MDM2 gene that attenuates the function of the p53 protein. Overall, approximately 70% of pancreatic NETs have one or more of these genetic changes. These findings suggest that the negative regulation of p53 function could be an important mechanism for the initiation and/or progression of pancreatic NETs, and reactivation of p53 could be a potential therapeutic strategy for patients with this disease.
| S-EPMC2943645 | biostudies-literature
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Project description:In the phase III RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), non-functional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio, 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in the everolimus arm vs 3.6 (1.9-5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (?5% incidence) grade 3-4 drug-related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well-differentiated, non-functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 cohort. These results support the use of everolimus in patients with advanced, non-functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783).
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Project description:IntroductionRecent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens.Materials and methodsThis was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR).ResultsTreatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months.ConclusionAmong patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy.Implications for practiceHigh-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.
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Project description:BackgroundSunitinib prolonged progression-free survival (PFS) versus placebo in patients with metastatic pancreatic neuroendocrine tumors (panNETs) in a phase III trial. The efficacy and safety of sunitinib in patients with panNETs were confirmed in an open-label phase IV trial.ObjectiveTo assess the clinical benefit with sunitinib using the combined data from these trials.Patients and methodsAn updated overall survival (OS) in patients with panNETs for the phase IV trial was provided, and an analysis of results from the sunitinib-treated combined cohort from the phase III and IV trials (combined cohort) was conducted to assess PFS, OS, and objective response rate (ORR).ResultsThe updated median OS for the phase IV trial was 54.1 months (95% CI 37.9-not reached). Investigator-assessed median PFS for the combined cohort (n = 102) was 12.9 months (95% CI 7.4-16.7) with a significant benefit versus placebo in the phase III trial (n = 35) (HR 0.429; 95% CI 0.245-0.752; p = 0.001). Median OS could not be calculated for the combined cohort or placebo group due to the high number of patients censored; however, the estimated HR of 0.303 (CI 0.100-0.921; p = 0.013) favored sunitinib. ORR for the combined cohort was 16.7% (95% CI 10.0-25.3). Sunitinib was well tolerated in both trials with a safety profile similar to previously seen in other studies.ConclusionsThe combined analysis of these studies confirms the objective tumor responses and improvements in PFS observed in the initial phase III trial, providing further support for the clinical benefit of sunitinib in patients with advanced panNETs. CLINICALTRIALS.Gov identifiersNCT00428597 and NCT01525550.
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