An Italian real-world multicenter study of patients with advanced mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) of the gastro-entero-pancreatic system treated with chemotherapy.

PURPOSE: The aim of this study is to describe the clinical management of an Italian series of patients with advanced gastro-entero-pancreatic (GEP) MiNENs treated in clinical practice. METHODS: Clinical records of patients from four Italian referral Centers were retrospectively analyzed to correlate clinical/biological data with clinical outcomes. All the surgical specimens were centrally reviewed. RESULTS: Clinical data and surgical samples of 51 patients during 1995-2015 were analyzed. Sites of origin were: 32 colorectal, 14 gastro-esophageal, and 5 pancreatobiliary. Twenty-one out of fifty-one (42.2%) developed metachronous distant metastases. Only 5/51 (9.8%) patients received peri-operative therapy, and 23/51 (45.1%) first-line chemotherapy, mostly fluoropyrimidines/oxaliplatin. The NEN component was poorly differentiated in the whole population. Patients with Ki67 index < 55% in the NEC component had a significantly longer median overall survival (OS) (35.3 months; 95% CI 27.1-41.0) than those with Ki67 ≥ 55% (11.9 months; 95% CI 9.1-14.0) P = 0.0005. The median OS was 14 months (95% CI 10.1-19.1) in the whole cohort, with 11.4 months (95% CI 6.2-20.2) in patients who received a first-line therapy. CONCLUSION: This study confirms that GEP-MiNENs represent a complex disease and that over the past years the clinical management has been predominantly guided by the subjective judgment of the clinicians. Although, in this series, the NEC component appeared mostly responsible for the systemic spread and prognosis on the whole neoplasm, the lack of strong prognostic and predictive factors universally recognized seems to condition their management so far. Future prospective clinical and biomolecular studies could help clinicians to improve clinical management of GEP-MiNENs.

Efficacy and Safety of Lanreotide Autogel and Temozolomide Combination Therapy in Progressive Thoracic Neuroendocrine Tumors (Carcinoid): Results from the Phase 2 ATLANT Study.

INTRODUCTION: Lanreotide autogel (LAN) and temozolomide (TMZ) are guidelines-recommended monotherapies for thoracic neuroendocrine tumors (carcinoids; T-NETs), but prospective data for both combined and monotherapies are lacking. ATLANT (NCT02698410) evaluated efficacy and safety of LAN/TMZ in progressive T-NETs. METHODS: ATLANT was a 12-month, Italian, phase 2, single-arm, open-label, multicenter pilot study. Eligible patients had unresectable, locally advanced/metastatic, well-/moderately differentiated T-NETs with radiological progression. Patients received subcutaneous LAN 120 mg every 28 days and oral TMZ 250 mg/day for 5 consecutive days every 28-day cycle. Main endpoints are disease control rate (DCR) at 9 months (primary; investigator-assessed), median progression-free survival (PFS), biomarkers, and safety. RESULTS: The number of patients was 40; 60% were male. Primary tumor site was lung (90%) and thymus (10%). Carcinoid type was typical (20.0%) and atypical (52.5%). DCR at 9 months was 35.0% (95% confidence interval (CI) 20.63-51.68; nonacceptability threshold ≤10%, p < 0.0001; not significantly above clinically relevant threshold ≥30%, p = 0.2968). DCR between 7.5 and 10.5 months (sensitivity analysis) was 45.0% (95% CI: 29.26-61.51) and clinically relevant (p = 0.0320 at ≥30% threshold). Median PFS was 37.1 (95% CI: 24.1-52.9) weeks. No association was observed between biomarker variations (chromogranin A, neuron-specific enolase, somatostatin receptor type-2, Ki-67, 6-O-methylguanine-DNA-methyl-transferase) and DCR or PFS. Most patients (97.5%) had treatment-emergent adverse events (TEAEs); 72.5% had treatment-related TEAEs. TEAEs were mainly grade 1/2. No unanticipated TEAEs were reported. CONCLUSIONS: This study showed that the LAN/TMZ combination has promising efficacy in progressive T-NETs, and was well tolerated. Larger studies are warranted to support the clinical benefits of LAN/TMZ in patients with T-NETs.

[177Lu]Lu-DOTA-TATE versus standard of care in adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs): a cost-consequence analysis from an Italian hospital perspective.

PURPOSE: To assess and compare clinical outcomes and costs, to the Italian healthcare system, of three therapeutic options approved in the management of adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs). METHODS: We compared the efficacy, safety, and costs of [177Lu]Lu-DOTA-TATE, everolimus (both originator and generic products), and sunitinib in patients with advanced GEP-NETs (NET G1 and G2) that had progressed following treatment with somatostatin analogs (SSAs). A cost-consequence model was developed and validated by a panel of clinical experts from three NET reference centres in Italy. The clinical outcomes included in the model were median progression-free survival and the incidence of grade 3 or 4 adverse events (AEs), as reported in pivotal clinical trials. The costs for acquisition and administration of each treatment, and of managing AEs, were calculated from the perspective of the Italian national health service. Treatment costs per progression-free month were calculated separately for patients with NETs of pancreatic (PanNETs; all three treatments) and gastrointestinal (GI-NETs; [177Lu]Lu-DOTA-TATE and everolimus only) origin. RESULTS: In patients with PanNETs, total costs per progression-free month were €2989 for [177Lu]Lu-DOTA-TATE, €4975 for originator everolimus, €3472 for generic everolimus, and €5337 for sunitinib. In patients with GI-NETs, total costs per progression-free month were €3189 for [177Lu]Lu-DOTA-TATE, €4990 for originator everolimus, and €3483 for generic everolimus. CONCLUSIONS: [177Lu]Lu-DOTA-TATE was associated with lower costs per progression-free month versus relevant treatment options in patients with GI-NETs or PanNETs (NET G1-G2; progressed following SSA treatment), although acquisition and administration costs are higher. These findings provide further economic arguments in the overall context of treatment decision-making.

Cyclin-dependent Kinases 4/6 Inhibitors in Neuroendocrine Neoplasms: from Bench to Bedside.

PURPOSE OF REVIEW: Cyclin-dependent kinases (CDKs) are key regulators that play an important role in cell division. Palbociclib, ribociclib and abemaciclib showed significant antitumor activity in several malignancies and, recently, also a myeloprotective effect for trilaciclib when added to chemotherapy. The purpose of this review is to highlight the current evidence for CDK4/6 inhibitors in neuroendocrine neoplasms (NENs). RECENT FINDINGS: Preclinical results showed a promising antitumor activity of CDK4/6 inhibitors in neuroendocrine tumors (NETs), but so far, the very few small clinical trials did not show a strong impact on progression free survival (PFS) and objective response in NETs. Meanwhile, the CDK4/6 inhibitor trilaciclib revealed significant effects in reducing chemotherapy-induced myelosuppression in small cell lung cancer (SCLC). Up to date, CDK4/6 inhibitors are still considered investigational in NETs as antitumor agents, whereas trilaciclib can be used in the routine clinical practice in extensive stage SCLC patients for reducing myelotoxicity of standard chemotherapy.

Antiproliferative Systemic Therapies for Metastatic Small Bowel Neuroendocrine Tumours.

OPINION STATEMENT: Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies with rising incidence and prevalence. Outcome and therapy of small bowel neuroendocrine tumours (SBNETs) is variable, depending on the grade, differentiation, tumour burden, as well as the site of the tumour origin. Because of this, multidisciplinary approach is essential. Large randomized clinical trials, with somatostatin analogues (PROMID, CLARINET) or with peptide receptor radionuclide therapy (PRRT) with 177-lutetium (NETTER-1 trial) as well as the mammalian target of rapamycin inhibitor (mTOR) everolimus (RADIANT trials), represent milestones for the medical management of unresectable grade 1 and 2 SBNETS over the last decade. Novel therapies, such as tyrosine kinase inhibitors (TKI), are on the cutting edge. However, multiple unsolved questions remain. This review provides a comprehensive review of the main systemic therapeutic options for advanced SBNETs and discusses the latest guideline recommendations for palliative treatment.

Morphological Factors Related to Nodal Metastases in Neuroendocrine Tumors of the Appendix: A Multicentric Retrospective Study.

OBJECTIVE: The aim of this study was to evaluate clinical and morphological features related to nodal involvement in appendiceal neuroendocrine tumors (NETs), to identify patients who should be referred for oncological radicalization with hemicolectomy. BACKGROUND: Appendiceal NETs are usually diagnosed accidentally after appendectomy; the indications for right hemicolectomy are currently based on several parameters (ie, tumor size, grading, proliferative index, localization, mesoappendiceal invasion, lymphovascular infiltration). Available guidelines are based on scarce evidence inferred by small, retrospective, single-institution studies, resulting in discordant recommendations. METHODS: A retrospective analysis of a prospectively collected database was performed. Patients who underwent surgical resection of appendiceal NETs at 11 tertiary Italian centers, from January 1990 to December 2015, were included. Clinical and morphological data were analyzed to identify factors related to nodal involvement. RESULTS: Four-hundred fifty-seven patients were evaluated, and 435 were finally included and analyzed. Of them, 21 had nodal involvement. Grading G2 [odds ratio (OR) 6.04], lymphovascular infiltration (OR 10.17), size (OR 18.50), and mesoappendiceal invasion (OR 3.63) were related to nodal disease. Receiver operating characteristic curve identified >15.5 mm as the best size cutoff value (area under the curve 0.747). On multivariate analysis, grading G2 (OR 6.98), lymphovascular infiltration (OR 8.63), and size >15.5 mm (OR 35.28) were independently related to nodal involvement. CONCLUSIONS: Tumor size >15.5 mm, grading G2, and presence of lymphovascular infiltration are factors independently related to nodal metastases in appendiceal NETs. Presence of ≥1 of these features should be considered an indication for oncological radicalization. Although these results represent the largest study currently available, prospective validation is needed.

Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues.

BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Carboplatin in Combination with Oral or Intravenous Etoposide for Extra-Pulmonary, Poorly-Differentiated Neuroendocrine Carcinomas.

BACKGROUND: Carboplatin-etoposide (CarboEtop) is a 1st-line option for patients with advanced extra-pulmonary (EP), poorly-differentiated (PD) neuroendocrine carcinoma (NEC). Different schedules are used in clinical practice and randomised evidence is lacking. OBJECTIVES: To provide real-life outcomes of carboplatin combined with oral or intravenous (IV) etoposide (Etop) in advanced EP-PD-NEC, from 2 specialist centres. METHODS: Activity/efficacy/toxicity data of CarboEtop were collected retrospectively and analysed. RESULTS: We identified 113 patients; median age: 65.8 years; male: 64%; gastro-entero-pancreatic origin: 54%; stage IV: 90%; median Ki-67: 70%; median follow-up: 11.5 months. A total of 123 courses of CarboEtop (oral: 45%; IV: 55%) were administered; 106 (86%) 1st-line, 16 (13%) 2nd-line, and 1 (1%) 3rd-line. Disease control rate: 74.5% in 1st-line and 69.2% in 2nd/3rd-line, with no significant difference between oral and IV Etop in 1st-line (69.8 vs. 80.8%, p = 0.237). Median progression-free survival (PFS): 6.0 and 4.5 months in 1st-line and 2nd/3rd-line, respectively. Overall survival (OS): 11.5 and 12.5 months in 1st-line and 2nd/3rd-line, respectively. The schedule (oral versus IV Etop) did not impact on 1st-line PFS (5.6 vs. 6.2 months, p = 0.179), although there was a trend towards shorter OS (8.9 vs. 12.1 months, p = 0.069). Liver metastases correlated with worse 1st-line PFS (p = 0.015) and 1st-line OS (p < 0.001) on multivariable analysis. The commonest grade 3-4 adverse event was myelosuppression (49%), with comparable toxicity between oral and IV Etop, except for venous thromboembolism (12.5 vs. 1.7%, p = 0.04). CONCLUSIONS: CarboEtop for advanced EP-PD-NEC is active, effective, and well-tolerated. Oral and IV Etop schedules are associated with comparable toxicity; activity should be compared in larger cohorts.

Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study.

INTRODUCTION: Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. AIM: To evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. PATIENTS AND METHODS: Retrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th-75th IQR). RESULTS: Eighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3%) had received three or more therapeutic regimens before sunitinib, with 24 patients (30%) having been treated with four previous treatments. Median PFS was 10 months. Similar risk of progression was observed between NET G1 and NET G2 tumors (median PFS 11 months and 8 months, respectively), and between patients who had received ≥ 3 vs ≤ 2 therapeutic approaches before sunitinib (median PFS 9 months and 10 months, respectively). DC rate was 71.3% and SD was the most frequent observed response, occurring in 43 pts (53.8%). Overall, 59 pts (73.8%) experienced AEs, which were grade 1-2 in 43 of them (72.9%), grade 3 in 15 pts (25.4%), and grade 4 in one patient (1.7%). Six pts (7.5%) stopped treatment due to toxicity. CONCLUSIONS: The present real-world experience shows that sunitinib is a safe and effective treatment for panNETs, even in the clinical setting of heavily pre-treated, progressive diseases.

Everolimus in Combination with Octreotide Long-Acting Repeatable in a First-Line Setting for Patients with Neuroendocrine Tumors: A 5-Year Update.

BACKGROUND: We previously presented data of this multicentric, phase II study showing that everolimus plus octreotide long-acting repeatable (LAR) for advanced neuroendocrine neoplasms (NENs), in the first line setting, is an active and safe treatment. We now present updated data at 5 years. METHODS: Patients with advanced well-differentiated, previously untreated neuroendocrine tumors of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg plus everolimus 10 mg/day. The primary endpoint was the objective response rate (ORR). We performed an analysis of "long responder" patients and of time to progression (TTP) and overall survival (OS) at 5 years. RESULTS: Fifty patients were enrolled; the primary tumor site was: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum/duodenum (2 patients), and unknown (14 patients). Seventeen (34%) of these patients have received treatment for more than 2 years. The median exposure to study drugs was 519.5 days (range 48-2,024). Currently 3 patients are still in treatment. The ORR (partial response + complete response) was 18% (95% confidence interval [CI] 7.4-28.6): complete response 1 patient (2%), partial response 8 patients (16%), stable disease 37 patients (74%). The median TTP was 33.6 months (95% CI 18.7-41.2) and the median OS was 61.0 months (95% CI 49.8-not reached). CONCLUSION: In this update of clinical outcome at 5-year follow-up, everolimus plus octreotide has been shown to be active in advanced NENs. The current analysis showed a further prolongation of TTP and a long exposure to the study drug without major side effects in the long term.

The Clinicopathologic Heterogeneity of Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: Morphological Differentiation and Proliferation Identify Different Prognostic Categories.

BACKGROUND/AIMS: Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are defined as neuroendocrine neoplasms (NENs) with a Ki-67 index >20% according to the 2010 WHO classification. Some reports suggest that this category is heterogeneous. We retrospectively studied a series of 136 patients affected by grade 3 GEP-NECs with the aim to clarify the prognostic role of tumor morphological differentiation, proliferation, defect in mismatch repair proteins (MMRd), CD117 expression, and site of origin. The primary endpoint was the correlation between these parameters and the overall survival (OS). METHODS: Univariate and multivariable Cox proportional hazards regression analyses were used to assess the prognostic significance of various clinical and histopathologic features. RESULTS: With a median follow-up of 81 months, the median OS was 12.9 months. At multivariate analysis, morphological differentiation, Ki-67 index, MMRd, stage, and CD117 expression were independent prognostic markers in NECs. Three different prognostic categories of NECs were identified according to the degree of morphologic differentiation (well vs. poorly differentiated) and Ki-67 index (<55% vs. ≥55%). On this basis, median OS was 43.6 months in well-differentiated neoplasms with a Ki-67 index 20-55% (named type A), 24.5 months in poorly differentiated neoplasms with a Ki-67 index 20-55% (type B), and 5.3 months (p < 0.0001) in poorly differentiated neoplasms with a Ki-67 index ≥55% (type C). CONCLUSIONS: The present study suggests that GEP-NECs represent a heterogeneous group of neoplasms which can be better classified in different prognostic categories using both tumor morphology and Ki-67 index.

Resection of the Primary Tumor Followed by Peptide Receptor Radionuclide Therapy as Upfront Strategy for the Treatment of G1-G2 Pancreatic Neuroendocrine Tumors with Unresectable Liver Metastases.

BACKGROUND: A low burden of disease represents an independent favorable prognostic factor of response to peptide receptor radionuclide therapy (PRRT) in patients affected by gastro-entero-pancreatic neuroendocrine tumors. However, it is not clear whether this is due to a lower diffusion of the disease or thanks to debulking surgery. METHODS: From 1996 to 2013 those patients diagnosed with G1-G2 pancreatic neuroendocrine tumor (PNET) and synchronous liver metastases who were not deemed eligible for liver radical surgery but were eligible to receive upfront PRRT were prospectively included in the study. Two groups of comparison were identified: those submitted for primary tumor resection before PRRT and those who were not. The outcome was evaluated as: objective response to PRRT (OR), progression-free survival (PFS), and overall survival (OS). RESULTS: Of the 94 subjects, 31 were previously submitted for primary tumor resection. After propensity score adjustments, patients who underwent surgery before PRRT showed higher stabilization or objective responses after PRRT (p = .006), and this translated into a better median PFS (70 vs. 30 months; p = .002) and OS (112 vs. 65 months; p = .011), for operated versus nonoperated patients, respectively. At multivariate analysis, operated patients showed a statistically significantly improved PFS: HR, 5.11 (95 % CI 1.43-18.3); p = .012, whereas Ki-67 in continuous fashion was correlated significantly with OS: 1.13 (95 % CI 1-1.27); p = .048. CONCLUSIONS: Primary tumor resection prior to PRRT can be safely proposed in G1-G2 PNETs with diffuse liver metastases because it seems to enhance response to PRRT and to improve significantly PFS.

Risk and Protective Factors for Small Intestine Neuroendocrine Tumors: A Prospective Case-Control Study.

BACKGROUND: The incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, but few studies have investigated risk factors for their occurrence, suggesting that family history (FH) of any cancer, smoking and previous cholecystectomy are associated with an increased risk. Such studies investigated small series or examined cancer registries without direct interviews. AIM: We therefore aimed at clarifying risk and protective factors for the occurrence of sporadic SI-NETs. SUBJECTS AND METHODS: We performed a multicenter case-control study. Patients with a histologic diagnosis of SI-NETs were prospectively evaluated, excluding familial syndromes. Controls with non-neoplastic/non-chronic disorders seen at gastrointestinal outpatients clinics were matched for sex and age (4:1). All subjects were directly interviewed by means of a specific questionnaire on potential risk and protective factors. Cases and controls were compared by Fisher's test or Student's t test for categorical or continuous variables. Explanatory variables were analyzed by simple logistic regression analysis. A multiple logistic regression analysis was performed with an Enter model; p < 0.05 was considered significant. RESULTS: 215 SI-NET patients and 860 controls were enrolled. FH of colorectal cancer (CRC) (8.8 vs. 5.0%) and breast cancer (10.2 vs. 4.8%), heavy smoking (24.7 vs. 14.8%) and drinking >21 alcohol units per week (7.4 vs. 3.8%) were all significantly more frequent in SI-NET patients than in controls. Multivariate analysis showed that FH of CRC (OR 2.23, 95% CI 1.29-3.84, p = 0.003), FH of breast cancer (OR 2.05, 95% CI 1.13-3.69, p = 0.01) and smoking (OR 1.47, 95% CI 1.07-2.03, p = 0.01) and in particular heavy smoking (OR 1.94, 95% CI 1.29-3.84, p = 0.0008) were associated with an increased risk for carcinoid occurrence, while use of aspirin can be considered a protective factor (OR 0.20, 95% CI 0.06-0.65, p = 0.008). CONCLUSION: FH of colorectal and breast cancer as well as smoking seem to be risk factors for the development of SI-NETs, while use of aspirin might be a protective factor. These factors partially overlap with those associated with CRC, but are different from those previously associated with pancreatic neuroendocrine tumors. These findings may suggest that the mechanisms of carcinogenesis for endocrine cells in different sites can be specific and similar to those of their exocrine counterparts.

Oxaliplatin-Based Chemotherapy in Advanced Neuroendocrine Tumors: Clinical Outcomes and Preliminary Correlation with Biological Factors.

PURPOSE: The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs. METHODS: Clinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples. RESULTS: Seventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome. CONCLUSION: This analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors.

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.

Everolimus in combination with octreotide long-acting repeatable in a first-line setting for patients with neuroendocrine tumors: an ITMO group study.

BACKGROUND: Preclinical and clinical studies suggest synergistic activity between somatostatin analogues and mammalian target of rapamycin inhibitors. The activity and safety of everolimus was assessed in combination with octreotide long-acting repeatable (LAR) in patients with neuroendocrine tumors (NETs) of gastroenteropancreatic and lung origin. METHODS: This was a phase 2, multicenter trial using a Simon's 2-stage minimax design. Treatment-naive patients with advanced well-differentiated NETs of gastroenteropancreatic tract and lung origin received everolimus 10 mg daily, in combination with octreotide LAR 30 mg every 28 days. The primary endpoint was objective response rate (ORR). RESULTS: A total of 50 patients (median age, 60.5 years) were enrolled. Primary tumor sites were: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum and duodenum (2 patients), and unknown (14 patients). Thirteen patients (26%) had carcinoid syndrome. Treatment-related adverse events (AEs) were mostly grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, whereas grade 3 AEs included skin rash in 1 case (2%), stomatitis in 4 cases (8%), and diarrhea in 11 cases (22%). The ORR was 18%; 2% of patients had a complete response (CR), 16% a partial response (PR) and 74% achieved stable disease (SD). All CRs and all PRs as well as 92% of SDs had a duration ≥ 6 months. The clinical benefit (CR+PR+SD) was 92%. At a median follow-up of 277 days, median time to progression and overall survival were not reached. CONCLUSIONS: The everolimus-octreotide LAR combination was active and well tolerated in these previously treated patients with advanced NETs, suggesting a possible role as first-line treatment in patients with NET.

Real-world study of everolimus in advanced progressive neuroendocrine tumors.

Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs.

Cytogenetic follow-up of chromosomal mosaicism detected in first-trimester prenatal diagnosis.

OBJECTIVE: To contribute to the risk assessment of true fetal mosaicism after detection of a mosaic chromosomal anomaly in chorionic villus samples (CVS) in order to enable more effective counseling and pregnancy management. METHODS: We retrospectively reviewed 7112 consecutive CVS analyzed on both direct preparations and cultured cells. In 135 out of the 177 cases of mosaicism, we performed cytogenetic follow-up and determined the frequency of confined placental mosaicism (CPM) and true fetal mosaicism according to type and distribution of the cytogenetic abnormality. RESULTS: True fetal mosaicism was detected in 38 out of 135 cases (28.15%), confirming the higher incidence of CPM (71.85%). Confirmation rate of CV mosaicism depends on the combination of placental cell lineages affected, chromosome involved and mosaic versus non-mosaic chromosomal anomaly. The overall probability of fetal involvement significantly rises with involvement of mesenchymal cells: 5.88% abnormal cytotrophoblast, 20.96% abnormal mesenchyme and 58.97% anomalies in both tissues. CONCLUSION: Most of the mosaic findings at CVS are unreliable indicators of the fetal karyotype. Our study contributes to large series with cytogenetic information from the different tissues along the cytotrophoblast-extraembrional mesoderm-fetus axis in order to infer clinical relevance of the findings and to enable more effective genetic counseling.

Immunotherapy in the neoadjuvant treatment of gastrointestinal tumors: is the time ripe?

Immune checkpoint inhibitors (ICIs) revolutionized the management of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal (GI) cancers. Based on notable results observed in the metastatic setting, several clinical trials investigated ICIs as neoadjuvant treatment (NAT) for localized dMMR/MSI-H GI cancers, achieving striking results in terms of clinical and pathological responses and creating the opportunity to spare patients from neoadjuvant chemotherapy and/or radiotherapy and even surgical resection. Nevertheless, these impressive findings are mainly derived from small proof of concept phase II studies and there are still several open questions to address. Moreover, dMMR/MSI-H represents a limited subgroup accounting for less than 10% of GI cancers. Consequently, many efforts have been produced to investigate neoadjuvant ICIs also in mismatch repair-proficient/microsatellite stable (MSS) cancers, considering the potential synergistic effect in combining immune-targeted agents with standard therapies such as chemo and/or radiotherapy. However, results for combining ICIs to the standard of care in the unselected population are still unsatisfactory, without improvements in event-free survival in esophago-gastric adenocarcinoma for the addition of pembrolizumab to chemotherapy, and sometimes limited benefit in patients with locally advanced rectal cancer. Therefore, a major challenge will be to identify among the heterogenous spectrum of this disease, those patients that could take advantage of neoadjuvant immunotherapy and deliver the most effective treatment. In this review we discuss the rationale of NAT in GI malignancies, summarize the available evidence regarding the completed trials that evaluated this treatment strategy in both MSI-H and MSS tumors. Finally, we discuss ongoing studies and future perspectives to render neoadjuvant immunotherapy another arrow in the quiver for the treatment of locally advanced GI tumors.

Metabolomic profile of neuroendocrine tumors identifies methionine, porphyrin, and tryptophan metabolisms as key dysregulated pathways associated with patient survival.

OBJECTIVE: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways. DESIGN AND METHODS: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA). RESULTS: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs. CONCLUSIONS: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients.