Gastroenteropancreatic Neuroendocrine Carcinomas Research Articles

27O Lurbinectedin plus irinotecan in pre-treated gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs)

27O Lurbinectedin plus irinotecan in pre-treated gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs)

Gastroenteropancreatic neuroendocrine carcinoma in children and adolescents: a population-based study.

Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC) in children is an exceptionally rare and aggressive form of cancer. We aimed toconducta population-based cohort study to predict overall survival (OS) in pediatric patients with GEP-NEC. The Surveillance, Epidemiology, and End Results (SEER) database was employedto identify all pediatric patients with GEP-NECdiagnosed between 2000 and 2019.To create survival curves based on variouscriteria, Kaplane-Meier estimations were utilized. The log-rank test was used to compare survival curves.The variables associated with OSwere determined using Cox proportional-hazards regression. Furthermore, we developeda nomogram to predict overall survival in pediatric GEP-NECpatients. A total of 103 pediatric GEP-NEC patients were identified. The tumors primarily affected females (62.2%). The majority of GEP-NEC was found in the appendix (63.1%), followed by the pancreas (23.3%) and the intestinal tract (13.6%). The highest rates of localized stage (76.9%) and surgery (98.5%) were found in the NEC of appendix origin. However, pancreatic origins had the largest proportion of distant disease (66.7%) but the lowest percentage of surgery (37.5%). Overall 1-year, 3-year, and 5-year survival rates for all patients were 94.4%, 85.4%, and 85.4%, respectively. Tumors of pancreatic origin had the worst survival compared with those of the appendix and intestinal tract. The Cox proportional hazard regression revealed that only site was an important independent predictor of survival. Our study revealed that only the primary site was found to be the most important predictor of the OS in pediatric GEP-NEC. It's important to work closely with a multidisciplinary team, including oncologists, surgeons, and other specialists, to determine the most appropriate treatment plan for pediatric GEP-NEC.

Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas.

There is an ongoing debate about whether the management of gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) should follow the guidelines of small-cell lung cancer (SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart. We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing (NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC (LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes. We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas. Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC ( TERT amplification), colorectal NEC ( KRAS mutation), and bile tract NEC ( ARID1A mutation). The gene disparities between small-cell NEC (SCNEC) and large-cell NEC (LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/ RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in 22.2% of the patients, and they had longer progression-free survival (PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40 (0.21-0.75), P=0.006]. This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.

Utility of 68Ga-DOTATATE for Grade 3, Poorly Differentiated Gastroenteropancreatic Neuroendocrine Carcinoma

Utility of 68Ga-DOTATATE for Grade 3, Poorly Differentiated Gastroenteropancreatic Neuroendocrine Carcinoma

Gastroenteropancreatic neuroendocrine carcinoma tumor spheroid drug screen reveals vulnerability to tyrosyl-DNA phosphodiesterase 1 inhibitors

BackgroundGastroenteropancreatic neuroendocrine carcinomas are rare neoplasms with no effective treatments and poor prognosis. Few reliable preclinical models exist for the study of gastroenteropancreatic neuroendocrine carcinomas, limiting investigation of novel treatments. We used tumor spheroids from our recently established gastroenteropancreatic neuroendocrine carcinoma patient-derived xenograft models to systematically screen for compounds with diverse structures to identify potential new categories of therapeutic agents that can target gastroenteropancreatic neuroendocrine carcinomas. MethodsTumor spheroids were derived from our NEC913 and NEC1452 gastroenteropancreatic neuroendocrine carcinoma patient-derived xenograft models. Gastroenteropancreatic neuroendocrine carcinoma spheroids were screened against a library of 885 compounds from the National Cancer Institute Diversity Set VII collection. Cell viability was measured via AlamarBlue assay. After identification of potential therapeutic compounds, synergy screening of a selected group with temozolomide and doxorubicin was performed, and these combinations were further analyzed for γH2AX and phosphorylated-ERK proteins. ResultsWe identified 16 compounds that inhibit over 75% of gastroenteropancreatic neuroendocrine carcinoma spheroid survival. Seven are inhibitors of tyrosyl-DNA phosphodiesterase 1, a DNA repair enzyme working closely with the topoisomerase I complex. When combined with temozolomide or doxorubicin, the tyrosyl-DNA phosphodiesterase 1 inhibitor cytarabine increased the cytotoxic effects of these drugs on NEC1452 cells which was further evidenced by increasing γH2AX and decreasing phosphorylated-ERK in combination treatment compared to temozolomide alone. ConclusionBoth NEC913 and NEC1452 gastroenteropancreatic neuroendocrine carcinoma spheroid lines are useful preclinical models for drug testing. Our library screen revealed these gastroenteropancreatic neuroendocrine carcinoma spheroids are highly sensitive to a novel class of anti-cancer drugs that target nuclear genome stability.

Surgical treatment of stage IV gastroenteropancreatic neuroendocrine carcinoma: Experience and outcomes in the United States.

Surgery for metastatic gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) has not been well-studied. This retrospective cohort study describes patients in the United States with stage IV GEP-NEC and their survival outcomes segregated by surgery. Patients diagnosed with stage IV GEP-NEC from 2004 to 2017 in the National Cancer Database were categorized into three groups: no surgery, primary site or metastatic site ("single-site") surgery, and primary site and metastatic site ("multisite") surgery. Factors associated with surgical treatment were identified, and risk-adjusted overall survival of each group was compared. Of 4171 patients included, 958 (23.0%) underwent single-site surgery and 374 (9.0%) underwent multisite surgery. The strongest predictor of surgery was primary tumor type. Compared with no surgery, the risk-adjusted mortality reduction associated with single-site surgery ranged from 63% for small bowel (HR = 0.37, 0.23-0.58, p < 0.001) NEC to 30% for colon and appendix NEC (HR = 0.70, 0.61-0.80, p < 0.001), while the mortality reduction associated with multisite surgery ranged from 77% for pancreas NEC (HR = 0.23, 0.17-0.33, p < 0.001) to 48% for colon and appendix NEC (HR = 0.52, 0.44-0.63, p < 0.001). We observed an association between extent of surgical intervention and overall survival for patients with stage IV GEP-NEC. Surgical resection should be further investigated as a treatment option for highly-selected patients with this aggressive disease.

Impact of surgical approach on short- and long-term outcomes in gastroenteropancreatic neuroendocrine carcinomas

BackgroundLiterature is lacking on the impact of advancements in minimally invasive surgery (MIS) on outcomes for patients with gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs). Herein, we compared perioperative and oncologic outcomes among patients with GEP-NECs undergoing open, laparoscopic, and robotic resection. MethodsPatients with GEP-NECs diagnosed 2010-2019 were identified from the National Cancer Database (NCDB). We used the inverse probability of treatment weighting method to account for selection bias. Patients were stratified by surgical approach; and pairwise comparisons were conducted by analyzing short- and long-term outcomes. ResultsReceipt of MIS increased from 34.2% in 2010 to 67.5 % in 2019. Altogether, 6560 patients met study criteria: 3444 (52.5%) underwent open resection, 2783 (42.4%) underwent laparoscopic resection and 333 (5.1%) underwent robotic resection. Compared with open resection, laparoscopic or robotic resection were associated with shorter post-operative length of stay, reduced 30-day and 90-day post-operative mortality, and prolonged overall survival (OS). Compared with laparoscopic resection, robotic resection was associated with reduced 90-day post-operative mortality, however, there was no significant difference in OS. ConclusionThis NCDB analysis demonstrates that MIS approaches for treating GEP-NECs have become more common, with improved perioperative mortality, shorter post-operative length of stay and favorable OS, compared with open resection.

Investigation into the immune microenvironment of gastroenteropancreatic high-grade neuroendocrine carcinoma.

e16244 Background: Gastroenteropancreatic high-grade neuroendocrine carcinomas (GEP HG-NEC) are aggressive cancers with poor survival and limited therapies. Using high-throughput gene expression analysis, we report the tumor-immune system interactions within the tumor microenvironment (TME), differentially expressed genes based on age, tumor location, survival, and objective response rate (ORR) to systemic therapy with the aim to drive future effective therapy research. Methods: We evaluated patients diagnosed with GEP HG-NEC from 2010-2021 for a pilot study and included those with adequate tumor samples. RNA was analyzed using the NanoString nCounter PanCancer IO 360 panel. Logistic regression modeling was used for hypothesis testing associated with best overall response. Cox model was used for testing overall survival (OS). One-sided P values were calculated per the hypothesized positive association between immune signatures and improved clinical outcomes. Results: 21 patients were identified. Mean age 64 years (yrs) with a 2:1 gender ratio (M=14; F=7). Most common primary locations - pancreas (PNEC = 8) and esophagus (3). ORR = 78.6%. TME trends were dampened anti-cancer immune response in patients &gt;60 yrs old and &lt;6-month OS on treatment. TME gene signatures of age &gt;60 yrs (vs. &lt;60 yrs), were indicative of fewer neutrophils, myeloid cells, CD8+ T-cells and CD45+ cells. Downregulated genes in the &gt;60yr old population associated with dampened immune response - ICAM1, TNFAIP6, TWIST1, and PTGER4. A smaller natural killer (NK) cell gene signature was the only notable association with OS &lt;6 months (vs. &gt;6 month). Downregulated genes in &gt;6-month population were HK2 and REN while upregulated genes included CX3CR1, ZAP70, KLRK1, XCL1/2, and MMP7 (immunostimulatory). Increased immune infiltration was associated with prolonged OS, with elevated gene signature of T-cells, lymphoid cells, mast cells, and cytotoxic cells. Downregulated genes related to poor OS were HNF1A and ESR1 (immunosuppressive). A greater potential for a tumor adaptive immune resistance/response were noted; age &lt;60 yrs and prolonged OS having elevated TME PD-L1 and PD-1/TIGIT gene signatures respectively. PNEC was associated with elevated gene signatures of TME MHCII vs. non-PNEC. Upregulated genes in non-PNEC include CXCL2/3 while downregulated genes include TMEM173, IFI16 and RELN (diminished adaptive immune response). Conclusions: This pilot study identified trends in gene expression associated with clinical outcomes. While statistical significance was precluded by limited sample size, our results suggest trends toward increased TME immune cell infiltration in age &lt;60yrs and prolonged OS, increased potential for adaptive immune responses in PNEC, and elevated NK cell infiltration in patients with &gt;6 month OS. Rational drug development for affected patients should target these specific abnormalities.

Advances in the Treatment of Gastroenteropancreatic Neuroendocrine Carcinomas: are we moving forward?

Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive neoplasms of challenging clinical management. A small proportion of patients with early-stage disease may achieve long-term survival, but the majority of patients present with rapidly lethal metastatic disease. Current standard of care still follows the treatment paradigm of small-cell lung cancer (SCLC), a far more common G3 NEN, although emerging molecular and clinical data increasingly question this approach. In this manuscript we will briefly summarize epidemiology and prognosis of GEP NECs to emphasize the very low incidence, aggressive nature and orphan status of this tumor entity. We will also discuss the current pathological classification and its limitations, as well as recent data on their differential biological background as compared to SCLC, and its potential implications for patients care. Then, we will review the standard of care of systemic therapy, basically focused on platinum-based cytotoxic chemotherapy, including some recent randomized trials providing evidence regarding efficacy of irinotecan vs etoposide platinum-doublets. Finally, we will present a comprehensive overview of novel therapeutic strategies in current clinical development, including recently reported data on immunotherapy, tumor-agnostic therapies (microsatellite instability, high tumor mutational burden, NTRK and RET gene fusions, BRAF or KRAS inhibitors) and additional treatment strategies targeting other tumor vulnerabilities (i.e. Notch pathway, novel targets for radioligand therapy), and provide some insights regarding unmet needs and future perspectives to improve patient's care and prognosis.

Mutation Spectrum in Liquid Versus Solid Biopsies From Patients With Advanced Gastroenteropancreatic Neuroendocrine Carcinoma.

Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor prognosis. Most GEP-NEC are diagnosed with metastatic disease, with only minor biopsies available for molecular diagnostics. We assessed the applicability of liquid biopsies for molecular profiling of GEP-NEC. We performed massive parallel sequencing of 76 cancer-related genes in circulating tumor DNA from 50 patients with advanced GEP-NEC and compared findings to previous analyses of solid tumor biopsies from the same patients. Plasma samples were collected before therapy, and the median time span between blood and tissue sampling was 25 days. We detected 178 somatic mutations in the liquid biopsies, 127 (71%) were also detected in the solid biopsies, whereas 51 (29%) were unique to the liquid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (single nucleotide variants) in solid biopsies, of which 127 (64%) were also now detected in liquid biopsies. In exploratory subgroup assessments, concordance was higher in patients with liver metastases (P = 1.5 × 10-5) and increasing with level of liver involvement (P = 1.2 × 10-4). The concordance was similar between GEP-NEC with different primary sites, except being lower in esophageal cases (P = .001). Concordance was not associated with tumor mutation burden. Tumor tissue mutations also detected in liquid biopsies was lower for MSI (40%) versus MSS tumors (70%; P = 7.8 × 10-4). We identified potentially targetable mutations in plasma of 26 (52%) of patients with GEP-NEC; nine patients (18%) had potentially targetable mutation detected only in liquid biopsies. Liquid biopsy analyses may be an applicable alternative to solid biopsies in GEP-NEC. Liquid biopsies may add additional mutations compared with tumor biopsies alone and could be useful for biomarker assessment in clinical trials for these patients.

Pilot Study of TQ Formula in Combination with Nivolumab and Ipilimumab in Metastatic Gastroenteropancreatic Neuroendocrine Carcinomas (GEP-NECAs)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Association of Surgery and Chemotherapy in Stage IV Gastroenteropancreatic Neuroendocrine Carcinoma

IntroductionThe survival benefit of chemotherapy for patients with metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) is well established. However, reasons for underutilization of chemotherapy are unknown. MethodsThe National Cancer Database (NCDB) was queried for metastatic GEP-NECs from 2009 to 2016. The cohort was stratified by patients who had received chemotherapy and who did not receive chemotherapy. Demographic, socioeconomic, clinical, and treatment characteristics were captured. Multivariable logistic regression examined factors associated with chemotherapy utilization. ResultsOf the 2367 stage IV GEP-NECs patients identified, 1647 (69.6%) received chemotherapy. Patients with primary site at colon and small bowel, age ≥75, no insurance, and ≥2 comorbidities were less likely to receive chemotherapy than patients with other primary sites, age <75, private insurance, and no comorbidities (P < 0.005). The small bowel and colon were the primary sites with the greatest percentage of patients who received surgery (46.4% and 41.8%, respectively). In these subgroup of patients, surgical intervention was also associated with lower probability of receiving chemotherapy (odds ratio = 0.60, P < 0.005). ConclusionsAbout 30% of patients with metastatic GEP-NECs did not receive chemotherapy. Primary site location and receipt of surgery were significantly associated with receipt of chemotherapy, with NECs in small bowel and colon being more likely to receive surgery and less likely to receive chemotherapy. While surgery may be considered on an individual basis, increasing efforts to ensure patients with colon or small bowel NECs receive guideline-concordant chemotherapy will positively impact survival. In addition, interventions to improve health insurance coverage to increase receipt of chemotherapy are warranted.

Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy

PurposeGastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) form a rare and remarkably heterogeneous group of tumors. Therefore, establishing personalized therapies is eminently challenging. To achieve progress in preclinical drug development, there is an urgent need for relevant tumor models.MethodsWe successfully established three gastroenteropancreatic neuroendocrine tumor (GEP-NET) cell lines (NT-18P, NT-18LM, NT-36) and two gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) cell lines (NT-32 and NT-38). We performed a comprehensive characterization of morphology, NET differentiation, proliferation and intracellular signaling pathways of these five cell lines and, in addition, of the NT-3 GEP-NET cell line. Additionally, we conducted panel sequencing to identify genomic alterations suitable for mutation-based targeted therapy.ResultsWe found that the GEP-NEN cell lines exhibit a stable neuroendocrine phenotype. Functional kinome profiling revealed a higher activity of serine/threonine kinases (STK) as well as protein tyrosine kinases (PTK) in the GEP-NET cell lines NT-3 and NT-18LM compared to the GEP-NEC cell lines NT-32 and NT-38. Panel sequencing revealed a mutation in Death Domain Associated Protein (DAXX), sensitizing NT-18LM to the Ataxia telangiectasia and Rad3 related (ATR) inhibitor Berzosertib, and a mutation in AT-Rich Interaction Domain 1A (ARID1A), sensitizing NT-38 to the Aurora kinase A inhibitor Alisertib. Small interfering RNA-mediated knock down of DAXX in the DAXX wild type cell line NT-3 sensitized these cells to Berzosertib.ConclusionsThe newly established GEP-NET and GEP-NEC cell lines represent comprehensive preclinical in vitro models suitable to decipher GEP-NEN biology and pathogenesis. Additionally, we present the first results of a GEP-NEN-specific mutation-based targeted therapy. These findings open up new potentialities for personalized therapies in GEP-NEN.

Establishment and validation of a clinicopathological prognosis model of gastroenteropancreatic neuroendocrine carcinomas.

BackgroundGastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are a rare, highly malignant subset of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, how to predict the prognosis of GEP-NECs by clinical features is still under study. This study aims to establish and validate a nomogram model of overall survival (OS) in patients with GEP-NECs for predicting their prognosis.MethodsWe selected patients diagnosed with GEP-NECs from the Surveillance, Epidemiology, and End Results (SEER) database and two Chinese hospitals. After randomization, we divided the data in the SEER database into the train cohort and the test cohort at a ratio of 7:3 and used the Chinese cohort as the validation cohort. The Cox univariate and multivariate analyses were performed to incorporate statistically significant variables into the nomogram model. We then established a nomogram and validated it by concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, the area under the curve (AUC), and the decision curve analysis (DCA) curve.ResultsWe calculated the nomogram C-index as 0.797 with a 95% confidence interval (95% CI) of 0.783–0.815 in the train cohort, 0.816 (95% CI: 0.794–0.833) in the test cohort and 0.801 (95% CI: 0.784–0.827) in the validation cohort. Then, we plotted the calibration curves and ROC curves, and AUCs were obtained to verify the specificity and sensitivity of the model, with 1-, 3- and 5-year AUCs of 0.776, 0.768, and 0.770, respectively, in the train cohort; 0.794, 0.808, and 0.799 in the test cohort; 0.922, 0.925, and 0.947 in the validation cohort. The calibration curve and DCA curves also indicated that this nomogram model had good clinical benefits.ConclusionsWe established the OS nomogram model of GEP-NEC patients, including variables of age, race, sex, tumor site, tumor grade, and TNM stage. This model has good fitting, high sensitivity and specificity, and good clinical benefits.

First-line treatment of camrelizumab combined with chemotherapy in advanced gastroenteropancreatic neuroendocrine carcinoma: Study protocol for a prospective, multicenter, phase II study.

BackgroundGastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a group of rare but highly aggressive malignancies. The standard chemotherapy regimens composed of etoposide and cisplatin/carboplatin (EP/EC) are of limited efficacy. This prospective, multicenter, phase II study is conducted to explore the effectiveness and safety of first-line anti-PD-1 antibody (camrelizumab) combined with chemotherapy in advanced GEP-NEC patients.MethodsPatients with unresectable or metastatic GEP-NEC will receive camrelizumab combined with standard first-line chemotherapy every 3 weeks (camrelizumab 200 mg, administered intravenously on day 1; etoposide 100 mg/m2, administered intravenously on days 1–3; cisplatin 75 mg/m2, administered intravenously on day 1 or carboplatin area under the curve 5 mg/ml per min, administered intravenously on day 1). All patients were naïve to systemic therapy in the advanced setting. The primary endpoint is a 6-month progression-free survival (PFS) rate. The secondary endpoints are objective response rate, PFS, overall survival and adverse reactions.DiscussionThis is the first study to investigate the therapeutic potential of camrelizumab plus chemotherapy for advanced GEP-NEC. It is expected that this trial will propose a new and effective treatment strategy for GEP-NEC in the first-line setting.Clinical Trial RegistrationThis trial is registered at the Chinese Clinical Trial Registry http://www.chictr.org.cn, identifier ChiCTR2100047314.Date of RegistrationJune 12, 2021.

Platinum-doublet chemotherapy for advanced gastroenteropancreatic neuroendocrine carcinoma: A systematic review and meta-analysis.

e16217 Background: Neuroendocrine carcinoma (NEC) is a poorly differentiated pathological neuroendocrine neoplasm exhibiting aggressive clinical behaviors; the most common extrapulmonary site is the gastroenteropancreatic (GEP) system. Treatment strategies for GEP-NEC are primarily based on those employed for small cell lung cancer, and platinum-doublet chemotherapy, such as platinum plus etoposide (EP) or platinum plus irinotecan (IP), has been widely used as initial systemic therapy for patients with advanced/metastatic disease; however, clinical data for GEP-NEC are chiefly derived from small-scale retrospective studies, and the reported efficacy is heterogenous among studies. Methods: We conducted a systematic database search using PubMed/MEDLINE and EMBASE. Eligible studies included randomized trials, single-arm trials, prospective observational studies, and retrospective studies documenting the clinical efficacy of platinum-doublet chemotherapy (EP and IP) for advanced GEP-NEC. The pooled overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were calculated and weighted using generic inverse variance in a random-effects meta-analysis model. Results: Based on initial screening and eligibility assessment, 19 studies with a combined total of 1,157 patients were identified through a systematic review. Studies included 3 comparative studies between EP and IP with 1 randomized phase II trial and 2 retrospective studies. The pooled ORR in all patients who received the platinum-doublet regimen was 49.1% (95% confidence interval [CI], 41.8–56.5), and subgroup analysis for EP and IP groups showed ORRs of 44.4% (95% CI, 35.9–53.0) and 59.4% (95% CI, 48.0–70.8), respectively. According to the three studies directly comparing EP to IP, the odds ratio of ORR using EP as reference was 1.95 (95% CI, 0.86–4.39, P = 0.11). The pooled median OS in all patients who received the platinum-doublet regimen was 12.9 (95% CI, 10.9–15.3) months, where EP and IP subgroups had median OS of 12.9 (95% CI, 10.8–15.4) and 12.9 (95% CI, 6.0–27.8) months, respectively. The pooled median PFS was 5.4 (95% CI, 4.5–6.4) months in all patients with platinum-regimen, 5.4 (95% CI, 4.5–6.5) months in the EP subgroup, and 4.0 (95% CI, 1.4–11.7) months in IP subgroup, respectively. Conclusions: This study was the first systematic review and meta-analysis assessing patients with GEP-NEC; it has revealed considerable ORR following platinum-doublet chemotherapy. EP and IP regimens can be reasonably employed in patients with advanced GEP-NEC. These results can serve as reference information for clinicians in deciding a suitable chemotherapy regimen. Larger randomized trials and individual patient data meta-analyses are warranted to obtain robust clinical evidence.

Platinum-doublet chemotherapy for advanced gastroenteropancreatic neuroendocrine carcinoma: a systematic review and meta-analysis

BackgroundPlatinum-doublet chemotherapy has been conventionally used for patients with advanced gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) but evidence of chemotherapy is based on studies with small sample sizes and remains scarce. Thus, we conducted a systematic review and meta-analysis to elucidate the efficacy of platinum-doublet chemotherapy for advanced GEP-NEC.MethodsWe performed a database search in PubMed/MEDLINE and EMBASE. Eligible studies were prospective and retrospective studies documenting the efficacy of platinum plus etoposide (EP) and platinum plus irinotecan (IP) for advanced GEP-NEC. Overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were pooled and weighted using generic inverse variance in a random-effects meta-analysis model.ResultsNineteen studies including 1157 patients were identified. The ORR of the platinum-doublet regimen, EP, and IP was 49.1% (95% confidence interval [CI], 41.8–56.5), 44.4% (95% CI: 35.9–53.0), and 59.4% (95% CI: 48.0–70.8). The pooled median OS of the platinum-doublet regimen, EP, and IP was 12.9 months (95% CI:10.9–15.3), 12.9 months (95% CI: 10.8–15.4), and 12.9 months (95% CI: 6.0–27.8), and the pooled median PFS of the platinum-doublet regimen, EP, and IP was 5.4 months (95% CI: 4.5–6.4), 5.4 months (95% CI 4.5–6.5), and 4.0 months (95% CI: 1.4–11.7), respectively.ConclusionConsiderable response rate and survival time of the platinum-doublet regimen for advanced GEP-NEC were observed. IP and EP regimens can be reasonably applicable and these results provide a reference for oncologists in deciding the suitable regimen for patients with advanced GEP-NEC.

Utility of KI-67 as a prognostic biomarker in pulmonary neuroendocrine neoplasms: a systematic review and meta-analysis.

ObjectivesKi-67, a marker of cellular proliferation, is associated with prognosis across a wide range of tumours, including gastroenteropancreatic neuroendocrine neoplasms (NENs), lymphoma, urothelial tumours and breast carcinomas. Its omission from the classification system of pulmonary NENs is controversial. This systematic review sought to assess whether Ki-67 is a prognostic biomarker in lung NENs and, if feasible, proceed to a meta-analysis.Research design and methodsMedline (Ovid), Embase, Scopus and the Cochrane library were searched for studies published prior to 28 February 2019 and investigating the role of Ki-67 in lung NENs. Eligible studies were those that included more than 20 patients and provided details of survival outcomes, namely, HRs with CIs according to Ki-67 percentage. Studies not available as a full text or without an English manuscript were excluded. This study was prospectively registered with PROSPERO.ResultsOf 11 814 records identified, seven studies met the inclusion criteria. These retrospective studies provided data for 1268 patients (693 TC, 281 AC, 94 large cell neuroendocrine carcinomas and 190 small cell lung carcinomas) and a meta-analysis was carried out to estimate a pooled effect. Random effects analyses demonstrated an association between a high Ki-67 index and poorer overall survival (HR of 2.02, 95% CI 1.16 to 3.52) and recurrence-free survival (HR 1.42; 95% CI 1.01 to 2.00).ConclusionThis meta-analysis provides evidence that high Ki-67 labelling indices are associated with poor clinical outcomes for patients diagnosed with pulmonary NENs. This study is subject to inherent limitations, but it does provide valuable insights regarding the use of the biomarker Ki-67, in a rare tumour.Prospero registration numberCRD42018093389.

Survival According to Primary Tumor Location, Stage, and Treatment Patterns in Locoregional Gastroenteropancreatic High-grade Neuroendocrine Carcinomas.

BackgroundAlthough the gastrointestinal tract (including the pancreas, gastroenteropancreatic (GEP) is the most common site for extrapulmonary neuroendocrine carcinoma (NEC), the current treatment patterns of locoregional GEP NEC and in particular, the role of surgical resection is unclear.MethodsData from the National Cancer Database between 2004 and 2016 were used for this study.ResultsOf 2314 GEP NEC cases (stages I–III), 52.5% were stage III. Colon was the most common site (30%); 30.9% of all cases were small cell morphology. Age, morphology, stage, and primary site were associated with significant differences in treatment patterns. Management of NEC mimicked that of adenocarcinomas arising at the respective sites: colon NEC most likely to be treated with surgery and chemotherapy; anal and esophageal NEC was primarily likely to receive chemotherapy and radiation, and rectal NEC mostly likely to receive trimodality therapy. However, 25%-40% of patients did not undergo surgical resection even at sites typically managed with curative resection, and there was a trend toward lesser resection over time. The prognostic impact of surgical resection was significant across all stages and correlated with variations in survival across primary sites. Even in patients undergoing chemoradiation, surgery was the only prognostic variable that significantly affected survival in stages I–II patients (HR 0.63) and showed a strong trend in stage III (HR 0.77) patients.ConclusionsTreatment patterns in GEP NEC vary considerably according to stage and primary tumor site. Surgery significantly improved survival in stages I–II patients and showed a strong trend in stage III patients regardless of primary tumor location and other perioperative therapies.

Optimization of the tumour response threshold in advanced gastroenteropancreatic neuroendocrine carcinomas treated with cisplatin/etoposide combined chemotherapy

ObjectivesTo identify early and more accurate imaging response criteria for computed tomography evaluation to define ‘responders’ in advanced gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) patients treated with cisplatin/etoposide combined chemotherapy. Materials and methodsThirty-seven patients with GEP-NEC treated with first-line cisplatin/etoposide (E/P) combined chemotherapy were enrolled in this study. Computed tomography scans of the chest, abdomen, and pelvis were performed at baseline, during the treatment course, and during follow-up. Tumour size was measured, and tumour response was evaluated by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Receiver operating characteristic (ROC) analysis was carried out among the patients who progressed during follow-up. Thresholds from −55% to + 5% were tested by Kaplan–Meier analysis to define “responders” for significantly improved progression-free survival (PFS). The overall survival rate was compared between these two groups. ResultsA reduction of 45% (vs. baseline) achieved the highest sensitivity (70%) and specificity (90%) by ROC analysis. This threshold divided patients into 15 responders and 22 nonresponders. Patients who were grouped as responders by the −45% threshold had a significantly longer PFS (11.06 months) than nonresponders (7.97 months, hazard ratio, 3.636; 95% confidence interval, 1.293–10.164). No significant difference was shown in overall survival between these two groups (29.1 vs. 21.4 months, P = 0.190). ConclusionA 45% reduction in target lesions may be considered to be a more reliable predictor than the RECIST 1.1 criteria in evaluating the outcome of GEP-NEC patients treated with E/P chemotherapy.