Surgery after sunitinib administration to improve survival of patients with advanced pancreatic neuroendocrine neoplasms.
Ontology highlight
ABSTRACT: Background
Little research is available regarding the treatments combining surgical resection with systemic chemotherapy for advanced pancreatic neuroendocrine neoplasm patients. We retrospectively elucidated whether sunitinib administration before surgery in advanced pancreatic neuroendocrine neoplasm (Pan-NEN) patients increases survival.Methods
This study included 106 of 326 Pan-NEN patients with distant metastases and/or unresectable locally advanced tumors who visited our department to receive sunitinib for more than 1 mo during April 2002 to December 2019. Risk factors for overall survival (OS) and disease-free survival (DFS) were analyzed.Results
The median duration of preoperative sunitinib administration and observation time after sunitinib were 6 and 26.5 mo, respectively. Of 106 patients, 31 (29.2%) underwent surgery following sunitinib administration. Hepatectomy, synchronous hepatopancreatectomy, pancreatectomy, and lymphadenectomy were performed for 13, 12, 5, and 1 patient, respectively. The 5-y OS rates in the resected and nonresected groups were 88.9% and 14.1%, respectively (P < .001). In the multivariate analysis, the absence of surgical resection following sunitinib (hazard ratio [HR], 13.1; P = .001), poor differentiation (HR, 5.5; P = .007), and bilateral liver metastases (HR, 3.7; P = .048) were independent risk factors for OS, although large liver tumor volumes were more evident in the nonresected group, as patient characteristics. The median DFS was 16.1 mo in 22 patients who underwent R0/1 resections, and risk factors for postoperative recurrence were Ki-67 index >7.8% (HR, 7.4; P = .02) and R1 resection (HR, 4.4; P = .04).Conclusion
Surgical resection after sunitinib administration improved OS in advanced Pan-NENs.
SUBMITTER: Murase Y
PROVIDER: S-EPMC8452477 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Pancreatic neuroendocrine neoplasms (panNENs) are relatively rare but their incidence has increased almost sevenfold over the last four decades. Neuroendocrine neoplasms are classified according to their histologic differentiation and their grade. Their grade is based on their Ki-67 proliferation index and mitotic index. Their prognosis is highly variable according to these elements and treatments also vary according to their classification. Surgery is the only curative treatment for localized and advanced panNENs and offers a better prognosis than non-surgical treatments. In the case of an advanced panNEN without the possibility of resection and/or ablation, medical treatment remains the cornerstone for improving survival and preserving quality-of-life. PanNENs are considered as chemosensitive tumors, unlike midgut neuroendocrine tumors. Thus, panNENs can be treated with chemotherapy, but targeted therapies and somatostatin analogs are also treatment options. The scarcity and heterogeneity of NENs make their management difficult. The present review aims to clarify the medical treatments currently available for advanced panNENs, based on their characteristics, and to propose a treatment algorithm.
| S-EPMC7355438 | biostudies-literature
Project description:BackgroundEverolimus and sunitinib have been approved for the treatment advanced pancreatic neuroendocrine tumors, but have not been compared to each other in a randomized trial and have not demonstrated prolonged overall survival compared to placebo. This study aimed to indirectly compare overall and progression-free among everolimus, sunitinib and placebo across separate randomized trials.MethodsA matching adjusted indirect comparison was conducted in which individual patient data from the pivotal trial of everolimus (n?=?410) were adjusted to match the inclusion criteria and average baseline characteristics reported for the pivotal trial of sunitinib (n?=?171). Prior to matching, trial populations differed in baseline performance status and prior treatments. After matching, these and all other available baseline characteristics were balanced between trials.ResultsCompared to the placebo arm in the sunitinib trial, everolimus was associated with significantly prolonged overall survival (HR?=?0.61, 95% CI?=?0.38-0.98, p?=?0.042).Compared to sunitinib, everolimus was associated with similar progression-free (hazard ratio for death (HR)?=?0.84, 95% CI?=?0.46-1.53, p?=?0.578) and overall survival (HR?=?0.81, 95% CI?=?0.49-1.31, p?=?0.383).ConclusionAfter adjusting for observed cross-trial differences, everolimus treatment was associated with longer overall survival than the placebo arm in the sunitinib trial for advanced pancreatic neuroendocrine tumors.
| S-EPMC4175512 | biostudies-literature
Project description:Microenvironment-related immune and inflammatory markers, when combined with established Ki-67 and morphology parameters, can improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Therefore, we evaluated the prognostic value of microenvironment and tumor inflammatory features (MoTIFs) in GEP-NENs. For this purpose, formalin-fixed paraffin-embedded tissue sections from 350 patients were profiled by immunohistochemistry for immune, inflammatory, angiogenesis, proliferation, NEN-, and fibroblast-related markers. A total of 314 patients were used to generate overall survival (OS) and disease-free survival (DFS) MoTIFs prognostic indices (PIs). PIs and additional variables were assessed using Cox models to generate nomograms for predicting 5-year OS and DFS. A total of 36 patients were used for external validation of PIs and nomograms' prognostic segregations. From our analysis, G1/G2 versus G3 GEP-NENs showed phenotypic divergence with immune-inflammatory markers. HLA, CD3, CD8, and PD-1/PD-L1 IHC expression separated G3 into two sub-categories with high versus low adaptive immunity-related features. MoTIFs PI for OS based on COX-2Tumor(T) > 4, PD-1Stromal(S) > 0, CD8S < 1, and HLA-IS < 1 was associated with worst survival (hazard ratio [HR] 2.50; 95% confidence interval [CI], 2.12-2.96; p < 0.0001). MoTIFs PI for DFS was based on COX-2T > 4, PD-1S > 4, HLA-IS < 1, HLA-IT < 2, HLA-DRS < 6 (HR 1.77; 95% CI, 1.58-1.99; p < 0.0001). Two nomograms were developed including morphology (HR 4.83; 95% CI, 2.30-10.15; p < 0.001) and Ki-67 (HR 11.32; 95% CI, 5.28-24.24; p < 0.001) for OS, and morphology (PI = 0: HR 10.23; 95% CI, 5.67-18.47; PI = 5: HR 2.87; 95% CI, 1.21-6.81; p < 0.001) and MoTIFs PI for DFS in well-differentiated GEP-NENs (HR 6.21; 95% CI, 2.52-13.31; p < 0.001). We conclude that G1/G2 to G3 transition is associated with immune-inflammatory profile changes; in fact, MoTIFs combined with morphology and Ki-67 improve 5-year DFS prediction in GEP-NENs. The immune context of a subset of G3 poorly differentiated tumors is consistent with activation of adaptive immunity, suggesting a potential for responsiveness to immunotherapy targeting immune checkpoints.
| S-EPMC6817832 | biostudies-other
Project description:Comparisons between everolimus and sunitinib regarding their efficacy and safety in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed the clinicopathological characteristics and outcomes in 92 patients with well-differentiated (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular targeted therapy (MTT) with everolimus or sunitinib, first- (73:19) or second-line (sequential; 12:22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs 12/19, P = 0.012). In PanNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P = 0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95% CI: 23.1-38.9) vs 9 months (95% CI: 0-18.5); log-rank P < 0.0001) in the whole cohort and the subset of PanNENs (log-rank P < 0.0001). Median PFS at second-line MTT was 12 months with everolimus (95% CI: 4.1-19.9) vs 13 months with sunitinib (95% CI: 9.3-16.7; log-rank P = 0.951). Treatment with sunitinib (HR: 3.47; 95% CI: 1.5-8.3; P value: 0.005), KI67 >20% (HR: 6.38; 95% CI: 1.3-31.3; P = 0.022) and prior chemotherapy (HR: 2.71; 95% CI: 1.2-6.3; P = 0.021) were negative predictors for PFS at first line in multivariable and also confirmed at multi-state modelling analyses. Side effect (SE) analysis indicated events of serious toxicities (Grades 3 and 4: n = 13/85 for everolimus and n = 4/41 for sunitinib). Discontinuation rate due to SEs was 20/85 for everolimus versus 4/41 for sunitinib (P = 0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus may be preferable to sunitinib when initiating MTT in progressive NENs.
| S-EPMC6528409 | biostudies-literature
Project description:ImportanceAlthough outcome of surgical resection of liver metastases from pancreatic neuroendocrine tumors (PNETs) has been extensively studied, little is known about surgery for locally advanced PNETs; it was listed recently by the European neuroendocrine tumor society as a major unmet need.ObjectiveTo evaluate the outcome of patients who underwent surgery for locally aggressive PNETs.Design, setting, and participantsThis retrospective single-center case series reviewed consecutive patients who underwent resection of T3/T4 PNETs at a single academic institution. Data collection occurred from 2003 to 2018. Data analysis was performed in August 2019.Main outcomes and measuresDisease-free survival (primary outcome) and overall mortality (secondary outcome) were assessed with Kaplan-Meier analysis. Recurrence risk (secondary outcome, defined as identification of tumor recurrence on imaging) was assessed with Cox proportional hazard models adjusting for covariates.ResultsIn this case series, 99 patients with locally advanced nondistant metastatic PNET (56 men [57%]) with a mean (SEM) age of 57.0 (1.4) years and a mean (SEM) follow-up of 5.3 (0.1) years underwent surgically aggressive resections. Of those, 4 patients (4%) underwent preoperative neoadjuvant treatment (including peptide receptor radionuclide therapy and chemotherapy); 18 patients (18%) underwent pancreaticoduodenectomy, 68 patients (69%) had distal or subtotal pancreatic resection, 10 patients (10%) had total resection, and 3 patients (3%) had other pancreatic procedures. Additional organ resection was required in 86 patients (87%): spleen (71 patients [71%]), major blood vessel (17 patients [17%]), bowel (2 patients [2%]), stomach (4 patients [4%]), and kidney (2 patients [2%]). Five-year disease-free survival was 61% (61 patients) and 5-year overall survival was 91% (91 patients). Of those living, 75 patients (76%) had an Eastern Cooperative Oncology Group score of less than or equal to 1 at last followup. Lymph node involvement (HR, 7.66; 95% CI, 2.78-21.12; P < .001), additional organ resected (HR, 6.15; 95% CI, 1.61-23.55; P = .008), and male sex (HR, 3.77; 95% CI, 1.68-8.97; P = .003) were associated with increased risk of recurrence. Functional tumors had a lower risk of recurrence (HR, 0.23; CI, 0.06-0.89; P = .03). Required resection of blood vessels was not associated with a significant increase recurrence risk.Conclusions and relevanceIn this case series, positive lymph node involvement and resection of organs with tumor involvement were associated with an increased recurrence risk. These subgroups may require adjuvant systemic treatment. These findings suggest that patients with locally advanced PNETs who undergo surgical resection have excellent disease-free and overall survival.
| S-EPMC7643030 | biostudies-literature
Project description:Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms arising from islets of the Langerhans in the pancreas. They can be divided into two groups, based on peptide hormone secretion, functioning and nonfunctioning PanNENs. The first group is characterized by different secreted peptides causing specific syndromes and is further classified into subgroups: insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma and tumors producing serotonin and adrenocorticotrophic hormone. Conversely, the second group does not release peptides and is usually associated with a worse prognosis. Today, although the efforts to improve the therapeutic approaches, surgery remains the only curative treatment for patients with PanNENs. The development of high-throughput techniques has increased the molecular knowledge of PanNENs, thereby allowing us to understand better the molecular biology and potential therapeutic vulnerabilities of PanNENs. Although enormous advancements in therapeutic and molecular aspects of PanNENs have been achieved, there is poor knowledge about each subgroup of functioning PanNENs.Therefore, we believe that combining high-throughput platforms with new diagnostic tools will allow for the efficient characterization of the main differences among the subgroups of functioning PanNENs. In this narrative review, we summarize the current landscape regarding diagnosis, molecular profiling and treatment, and we discuss the future perspectives of functioning PanNENs.
| S-EPMC9953748 | biostudies-literature
Project description:BackgroundThe WHO classified pancreatic neuroendocrine neoplasms in 2010 as G1, G2, and neuroendocrine carcinoma (NEC), according to the Ki67 labeling index (LI). However, the clinical behavior of NEC is still not fully studied. We aimed to clarify the clinicopathological and molecular characteristics of NECs.MethodsWe retrospectively evaluated the clinicopathological characteristics, KRAS mutation status, treatment response, and the overall survival of eleven pNEC patients diagnosed between 2001 and 2014 according to the WHO 2010. We subclassified WHO-NECs into well-differentiated NEC (WDNEC) and poorly differentiated NEC (PDNEC). The latter was further subdivided into large-cell and small-cell subtypes.ResultsThe median Ki67 LI was 69.1% (range 40-95%). Eleven WHO-NECs were subclassified into 4 WDNECs and 7 PDNECs. The latter was further separated into 3 large-cell and 4 small-cell subtypes. Comparisons of WDNEC vs. PDNEC revealed the following traits: hypervascularity on CT, 50% (2/4) vs. 0% (0/7) (P = 0.109); median Ki67 LI, 46.3% (40-53%) vs. 85% (54-95%) (P = 0.001); Rb immunopositivity, 100% (4/4) vs. 14% (1/7) (P = 0.015); KRAS mutations, 0% (0/4) vs. 86% (6/7) (P = 0.015); response rates to platinum-based chemotherapy, 0% (0/2) vs. 100% (4/4) (P = 0.067), and median survival, 227 vs. 186 days (P = 0.227).ConclusionsThe WHO-NEC category may be composed of heterogeneous disease entities, namely WDNEC and PDNEC. These subgroups tended to exhibit differing profiles of Ki67 LI, Rb immunopositivity and KRAS mutation, and distinct response to chemotherapy. Further studies for the reevaluation of the current WHO 2010 classification are warranted.
| S-EPMC4653242 | biostudies-literature
Project description:Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms with strong heterogeneity that have experienced an increasing incidence rate in recent years. For patients with locally advanced or distant metastatic PanNENs, systemic treatment options vary due to the different differentiations, grades and stages. The available options for systemic therapy include somatostatin analogs, mole-cularly targeted agents, cytotoxic chemotherapeutic agents, immune checkpoint inhibitors, and peptide receptor radionuclide therapy. In addition, the development of novel molecularly targeted agents is currently in progress. The sequence of selection between different chemotherapy regimens has been of great interest, and resistance to chemotherapeutic agents is the major limitation in their clinical application. Novel agents and high-level clinical evidence continue to emerge in the field of antiangiogenic agents. Peptide receptor radionuclide therapy is increasingly employed for the treatment of advanced neuroendocrine tumors, and greater therapeutic efficacy may be achieved by emerging radio-labeled peptides. Since immune checkpoint inhibitor monotherapies for PanNENs appear to have limited antitumor activity, dual immune checkpoint inhibitor therapies or combinations of antiangiogenic therapies and immune checkpoint inhibitors have been applied in the clinic to improve clinical efficacy. Combining the use of a variety of agents with different mechanisms of action provides new possibilities for clinical treatments. In the future, the study of systemic therapies will continue to focus on the screening of the optimal benefit population and the selection of the best treatment sequence strategy with the aim of truly achieving individualized precise treatment of PanNENs.
| S-EPMC9157622 | biostudies-literature
Project description:Several circulating biomarkers and single nucleotide polymorphisms (SNPs) have been correlated with efficacy and tolerability to antiangiogenic agents. These associations remain unexplored in well-differentiated, metastatic pancreatic neuroendocrine tumors treated with the multitargeted tyrosine kinase inhibitor sunitinib. We have assessed the effect on tumor response at 6 months, overall survival, progression-free survival and safety of 14 SNPs, and 6 soluble proteins. Forty-three patients were recruited. Two SNPs in the vascular endothelial growth factor receptor 3 (VEGFR-3) gene predicted lower overall survival: rs307826 with hazard ratio (HR) 3.67 (confidence interval [CI] 95%, 1.35-10.00) and rs307821 with HR 3.84 (CI 95%, 1.47-10.0). Interleukin-6 was associated with increased mortality: HR 1.06 (CI 95%, 1.01-1.12), and osteopontin was associated with shorter PFS: HR 1.087 (1.01-1.16), independently of Ki-67. Furthermore, levels of osteopontin remained higher at the end of the study in patients considered non-responders: 38.5 ng/mL vs. responders: 18.7 ng/mL, p-value=0.039. Dynamic upward variations were also observed with respect to IL-8 levels in sunitinib-refractory individuals: 28.5 pg/mL at baseline vs. 38.3 pg/mL at 3 months, p-value=0.024. In conclusion, two VEGFR-3 SNPs as well as various serum biomarkers were associated with diverse clinical outcomes in patients with well-differentiated pancreatic neuroendocrine tumors treated with sunitinib.
| S-EPMC6319342 | biostudies-literature
Project description:Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumors, but their incidental diagnosis has significantly increased due to the widespread use of imaging studies. Therefore, most PanNENs are now diagnosed when completely asymptomatic and in early stages. PanNENs are classified according to their grade (Ki-67 index) and can be functional (F-) or nonfunctional (NF-) depending on the presence or absence of a clinical, hormonal hypersecretion syndrome. The mainstay treatment of PanNENs is a surgery that is mostly curative but also associated with significant short- and long-term adverse events. Therefore, less invasive alternative locoregional treatment modalities are warranted. Recently, few case reports and two case series have described EUS-guided radiofrequency ablation (EUS-RFA) for the treatment of patients with both F-PanNENs and NF-PanNENs. If for F-PanNENs EUS-RFA can very easily become the standard of care, for NF-PanNENEs it is still controversial how to select patients for EUS-RFA. A balance between overtreatment (i.e., RFA/surgery in patients who will not progress) and undertreatment (locoregional treatments in patients with undetected metastases) needs to be found based on solid data. The decision should also take into account patients' comorbidity and risk of postoperative death, life expectancy, tumor location, risk of postoperative fistula and postoperative morbidity, and risk of long-term exocrine and/or endocrine insufficiency. To answer the important question on which a patient should be treated with EUS-RFA, properly designed studies to evaluate the efficacy of this treatment in large cohorts of patients with NF-PanNENs and to establish prognostic factors associated with treatment response are urgently needed.
| S-EPMC6714479 | biostudies-literature