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Background: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors such as everolimus. This post hoc pooled analysis assessed the potential impact of these events on the efficacy of everolimus., Methods: Patients with advanced, low- or intermediate-grade pancreatic, gastrointestinal, or lung neuroendocrine tumors received either oral everolimus at 10 mg/d or a placebo in the RAD001 in Advanced Neuroendocrine Tumors 3 (RADIANT-3) and RAD001 in Advanced Neuroendocrine Tumors 4 (RADIANT-4) trials. A landmark progression-free survival (PFS) analysis by central review was performed for patients treated for at least 16 weeks (n = 308) and according to the occurrence of any-grade adverse events (AEs) within this treatment period., Results: The overall PFS with everolimus from the pooled analysis was 11.4 months (95% confidence interval, 11.01-13.93 months), which was consistent with the findings of RADIANT-3 and RADIANT-4. Overall, 19.1% and 9.8% of patients in RADIANT-3 and 11.9% and 6.4% of patients in RADIANT-4 developed any-grade hyperglycemia and hypercholesterolemia, respectively (regardless of the study drug). The duration of everolimus exposure was longer in patients who developed these AEs versus patients without these AEs. Overall, 308 patients were exposed to treatment for at least 16 weeks (hyperglycemia, 39 of 269 patients; hypercholesterolemia, 20 of 288 patients). No association was observed between the development of these AEs and PFS (18.8 and 14.1 months with and without hyperglycemia, respectively, and 14.1 and 14.8 months with and without hypercholesterolemia, respectively)., Conclusions: Although limitations apply because of the small number of AEs observed, there was no significant impact of these AEs on PFS; this suggests similar efficacy in the presence or absence of these events., (© 2021 American Cancer Society.)

Purpose: Approved systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown limited capacity to reduce tumor burden and no antitumor activity after progression to targeted agents (TAs). We investigated the efficacy and safety of lenvatinib in patients with previously treated advanced GEP-NETs., Patients and Methods: This was a multicenter, single-arm, open-label, phase II trial with two parallel cohorts (ClinicalTrials.gov identifier: NCT02678780) involving 21 institutions in 4 European countries. Eligible patients had histologically confirmed advanced grade 1-2 pancreatic (panNET) or GI (GI-NET) NETs with documented tumor progression after treatment with a TA (panNET) or somatostatin analogs (GI-NET). Patients were treated with lenvatinib 24 mg once daily until disease progression or treatment intolerance. The primary end point was overall response rate by central radiology review. Secondary end points included progression-free survival, overall survival, duration of response, and safety., Results: Between September 2015 and March 2017, a total of 111 patients were enrolled, with 55 (panNET) and 56 (GI-NET) patients in each cohort. The median follow-up was 23 months. The overall response rate was 29.9% (95% CI, 21.6 to 39.6): 44.2% (panNET) and 16.4% (GI-NET). The median (range) duration of response was 19.9 (8.4-30.8) and 33.9 (10.6-38.3) months in the panNET and GI-NET groups, respectively. The median progression-free survival was 15.7 months (95% CI, 14.1 to 19.5). The most common adverse events were fatigue, hypertension, and diarrhea; 93.7% of patients required dose reductions or interruptions., Conclusion: We report the highest centrally confirmed response reported to date with a multikinase inhibitor in advanced GEP-NETs, with a particularly strong response in the panNET cohort. This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other TAs, suggesting the potential value of lenvatinib in the treatment of advanced GEP-NETs., Competing Interests: Jaume CapdevilaConsulting or Advisory Role: Bayer, Eisai, Sanofi, Exelixis, Novartis, Ipsen, Pfizer, Merck Serono, Advanced Accelerator Applications, LillySpeakers' Bureau: Bayer, Eisai, Sanofi, Novartis, Ipsen, Pfizer, Merck Serono, LillyResearch Funding: Eisai, AstraZeneca, Advanced Accelerator Applications, Novartis, Ipsen, Bayer, PfizerTravel, Accommodations, Expenses: Pfizer, Ipsen, Eisai Nicola FazioHonoraria: Novartis, Ipsen, Merck, Sanofi, Advanced Accelerator ApplicationsConsulting or Advisory Role: Novartis/Ipsen, Advanced Accelerator Applications, Pfizer, Ipsen, Merck Serono, MSD OncologyResearch Funding: Novartis, Merck Serono, Ipsen, MSDOther Relationship: Springer, Il Pensiero Scientifico Editore Carlos Lopez LopezHonoraria: Roche, Merck, Sanofi, Novartis, Pfizer, Eisai, Ipsen, Bayer, AstraZeneca, Servier, Bristol Myers Squibb, MSD Oncology, Advanced Accelerator ApplicationsConsulting or Advisory Role: Amgen, Roche, Sanofi, Merck, Servier, Pfizer, Ipsen, Bayer, Eisai, AstraZenecaResearch Funding: Amgen, Roche, Merck, Merck Sharp & Dohme, AstraZeneca Spain, Sanofi, Bayer, Ipsen, Eisai, Bristol Myers Squibb, Boehringer IngelheimTravel, Accommodations, Expenses: Roche, Pfizer, Merck, Servier, Amgen, Ipsen Alex TeuleHonoraria: Ipsen, Novartis, AAA HealthCare, PfizerConsulting or Advisory Role: AAA HealthCare Juan ValleHonoraria: IpsenConsulting or Advisory Role: Ipsen, Novartis, AstraZeneca, Merck, Agios, Pfizer, PCI Biotech, Incyte, Keocyt, QED Therapeutics, Pieris Pharmaceuticals, Genoscience Pharma, Mundipharma EDO GmbH, Wren Laboratories, Nucana, Servier, Debiopharm Group, Imaging Equipment Limited, Hutchison MediPharma, Zymeworks, Aptitude Health, Sirtex Medical, BaxterSpeakers' Bureau: Novartis, Ipsen, Nucana, Imaging Equipment Limited, Mylan, IncyteTravel, Accommodations, Expenses: Nucana, Pfizer, Lilly Nicholas ReedHonoraria: Novartis, Ipsen, Eisai, Roche, LillyConsulting or Advisory Role: Novartis, Ipsen, EisaiSpeakers' Bureau: RocheResearch Funding: Novartis, Ipsen, Exelixis, Lilly Enrique GrandeHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Genzyme, Advanced Accelerator Applications, Novartis, Pierre Fabre, Lexicon, Celgene, Janssen-Cilag, Astellas Pharma, AstraZeneca, Lilly, EUSA PharmaConsulting or Advisory Role: MSD, Pfizer, Ipsen, Roche, Bristol Myers SquibbResearch Funding: Roche, Pfizer, AstraZeneca, Ipsen, Molecular Templates, Lexicon, Astellas PharmaTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche/Genentech, Pfizer, Janssen-Cilag, Ipsen Rocio Garcia-CarboneroHonoraria: Ipsen, Roche, Sanofi, Servier, Novartis, Pfizer, Merck, PharmaMar, Advanced Accelerator Applications, Bristol Myers Squibb, AstraZeneca, Lilly, Boehringer Ingelheim, Gilead Sciences, Sysmex, Pierre Fabre, Midatech Pharma, Advanz Pharma, HMP, Bayer, MSDConsulting or Advisory Role: Ipsen, Novartis, Pfizer, HMP, Advanced Accelerator Applications, Bayer, PharmaMar, Merck, MSD, Pierre FabreResearch Funding: Pfizer, Bristol Myers Squibb, MSDTravel, Accommodations, Expenses: Roche, Merck Paula J FonsecaOther Relationship: Ipsen Jorge HernandoSpeakers' Bureau: Eisai, Ipsen, Roche, Acraf, Advanced Accelerator ApplicationsTravel, Accommodations, Expenses: Ipsen, Novartis, Advanced Accelerator Applications, Roche, AstraZeneca, Eisai Francesca SpadaConsulting or Advisory Role: Ipsen, Novartis, Advanced Accelerator ApplicationsSpeakers' Bureau: Ipsen, Novartis, Advanced Accelerator ApplicationsTravel, Accommodations, Expenses: Ipsen, Novartis, Advanced Accelerator Applications Vicente AlonsoConsulting or Advisory Role: Amgen, Sanofi/Regeneron, Ipsen, Servier, Merck SeronoTravel, Accommodations, Expenses: Merck Serono, Roche, Novartis, Amgen, Sanofi/Regeneron, Ipsen, Servier Alfredo BerrutiConsulting or Advisory Role: Janssen-Cilag, Astellas Pharma, AmgenSpeakers' Bureau: Janssen-Cilag, Astellas PharmaResearch Funding: Astellas Pharma, Janssen-CilagTravel, Accommodations, Expenses: Janssen-Cilag, Sanofi, Sanofi Adelaida La CastaTravel, Accommodations, Expenses: Amgen, Roche, MSD Oncology Sevilla IsabelConsulting or Advisory Role: Ipsen, Pfizer, AmgenSpeakers' Bureau: Ipsen, PharmaMar, Sanofi, AAA HealthCareTravel, Accommodations, Expenses: Ipsen Patrizia KumpResearch Funding: Bristol Myers SquibbTravel, Accommodations, Expenses: Ipsen Pablo GajateConsulting or Advisory Role: Ipsen, Roche, EisaiSpeakers' Bureau: IPSEN, Pfizer, Novartis, EisaiTravel, Accommodations, Expenses: Ipsen, Pfizer Ignacio MatosSpeakers' Bureau: MSDResearch Funding: ESMO Angela LamarcaConsulting or Advisory Role: EISAI, Nutricia, Ipsen, QED Therapeutics, RocheSpeakers' Bureau: Merck, Ipsen, Pfizer, Novartis, Incyte, Advanced Accelerator ApplicationsResearch Funding: Ipsen, RocheTravel, Accommodations, Expenses: Abbott Nutrition, Ipsen, Pfizer, Celgene, Novartis, Advanced Accelerator Applications, Sirtex Medical, Bayer, Delcath Systems, Mylan, NanoString Technologies Toni IbrahimConsulting or Advisory Role: EISAI, Novartis, SanofiTravel, Accommodations, Expenses: Ipsen, Pharmamar, NovartisNo other potential conflicts of interest were reported.

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., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: The RADIANT-4 randomized phase 3 study demonstrated significant prolongation of median progression-free survival (PFS) with everolimus compared to placebo (11.0 [95% CI 9.2-13.3] vs. 3.9 [95% CI 3.6-7.4] months) in patients with advanced, progressive, nonfunctional gastrointestinal (GI) and lung neuroendocrine tumors (NET). This analysis specifically evaluated NET patients with GI and unknown primary origin., Methods: Patients in the RADIANT-4 trial were randomized 2:1 to everolimus 10 mg/day or placebo. The effect of everolimus on PFS was evaluated in patients with NET of the GI tract or unknown primary site., Results: Of the 302 patients enrolled, 175 had GI NET (everolimus, 118; placebo, 57) and 36 had unknown primary (everolimus, 23; placebo, 13). In the GI subset, the median PFS by central review was 13.1 months (95% CI 9.2-17.3) in the everolimus arm versus 5.4 months (95% CI 3.6-9.3) in the placebo arm; the hazard ratio (HR) was 0.56 (95% CI 0.37-0.84). In the unknown primary patients, the median PFS was 13.6 months (95% CI 4.1-not evaluable) for everolimus versus 7.5 months (95% CI 1.9-18.5) for placebo; the HR was 0.60 (95% CI 0.24-1.51). Everolimus efficacy was also demonstrated in both midgut and non-midgut populations; a 40-46% reduction in the risk of progression or death was reported for patients in the combined GI and unknown primary subgroup. Everolimus had a benefit regardless of prior somatostatin analog therapy., Conclusions: Everolimus showed a clinically meaningful PFS benefit in patients with advanced progressive nonfunctional NET of GI and unknown primary, consistent with the overall RADIANT-4 results, providing an effective new standard treatment option in this patient population and filling an unmet treatment need for these patients., (© 2017 S. Karger AG, Basel.)

Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data., Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs)., Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%)., Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib., (© 2018 S. Karger AG, Basel.)

Well-established criteria for evaluating the response to treatment and the appropriate followup of individual patients are critical in clinical oncology. The current evidence-based data on these issues in terms of the management of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are unfortunately limited. This document by the Italian Association of Clinical Endocrinologists (AME) on the criteria for the follow-up of GEP-NEN patients is aimed at providing comprehensive recommendations for everyday clinical practice based on both the best available evidence and the combined opinion of an interdisciplinary panel of experts. The initial risk stratification of patients with NENs should be performed according to the grading, staging and functional status of the neoplasm and the presence of an inherited syndrome. The evaluation of response to the initial treatment, and to the subsequent therapies for disease progression or recurrence, should be based on a cost-effective, risk-effective and timely use of the appropriate diagnostic resources. A multidisciplinary evaluation of the response to the treatment is strongly recommended and, at every step in the follow-up, it is mandatory to assess the disease state and the patient performance status, comorbidities, and recent clinical evolution. Local expertise, available technical resources and the patient preferences should always be evaluated while planning the individual clinical management of GEP-NENs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

In the phase III RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), non-functional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio, 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in the everolimus arm vs 3.6 (1.9-5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (≥5% incidence) grade 3-4 drug-related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well-differentiated, non-functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 cohort. These results support the use of everolimus in patients with advanced, non-functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783)., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.

The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48). The response rate and toxicity were comparable in the two groups. However, patients in group A experienced more dose modifications than patients in group B. Median OS was 24 months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0-76.7; P < 0.0001). Patients who maintained a DI higher than 9 mg/day experienced a significantly longer OS and experienced a trend to higher response rate. Overall, our study results showed that both CD and DI of everolimus play a prognostic role for patients with advanced PNETs treated with everolimus. This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Metronomic therapy is characterized by the administration of regular low doses of certain drugs with very low toxicity. There have been numerous debates over the empirical approach of this regimen, but fewest side effects are always something to consider in order to improve patients' quality of life. Neuroendocrine tumors (NETs) are rare malignancies relatively slow-growing; therefore their treatment is often chronic, involving several different therapies for tumor growth control. Knowing that these tumors are highly vascularized, the anti-angiogenic aspect is highly regarded as something to be targeted in all patients harboring NETs. Additionally the metronomic schedule has proved to be effective on an immunological level, rendering this approach as a multi-targeted therapy. Rationalizing that advanced NETs are in many cases a chronic disease, with which patients can live for as long as possible, a systemic therapy with regular low doses and a very low toxicity is in many cases a judicious manner of pursuing stabilization. Metronomic schedule is usually correlated with chemotherapy in oncology, but other therapies, such as radiotherapy and biotherapy can be delivered in a metronomic like manner. This review describes clinical trials and case series involving metronomic therapies alone or in combination in patients with advanced NETs. Nowadays level of evidence about metronomic therapy in NETs is quite low, therefore future prospective clinical studies are needed to validate the metronomic approach in specific clinical settings., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population., Methods: In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783., Findings: Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0)., Interpretation: Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract., Funding: Novartis Pharmaceuticals Corporation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436)., Patients and Methods: In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1., Results: As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%)., Conclusion: BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2., Competing Interests: CV has received honoraria from Bayer, Novartis, and Ipsen. EB has received funding to attend ASCO 2013 and ESMO 2015. LA has received honoraria from Roche, Novartis, Ipsen, Merck, and Eli Lilly. MS has received research funding from Novartis. NF has received honoraria from Ipsen and Novartis, and research funding from Novartis. RB reports research funding from Novartis. WWdH has received research funding from Ipsen and Novartis. DD, ST, and PA are employees of Novartis. CM is an employee and shareholder of Novartis. All remaining authors (AT, HL, JC, MHK, MR, RAH, SKL) have declared no conflicts of interest. The study was funded by Novartis Pharmaceuticals Corporation and designed in conjunction with the steering committee. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

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., (© 2016 S. Karger AG, Basel.)

Background: No randomized trials have so far investigated the cost effectiveness of different methods for implantation and use of central venous ports in oncology patients., Patients and Methods: Overall, 403 patients eligible for receiving intravenous chemotherapy for solid tumours were randomly assigned to implantation of a single type of port, either through a percutaneous landmark access to the internal jugular vein, an ultrasound (US)-guided access to the subclavian vein, or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. Insertion and maintenance costs were estimated by obtaining the charges for an average implant and use, while the costs of the management of complications were analytically assessed. The total cost was defined as the purchase cost plus the insertion cost plus the maintenance cost plus the cost of treatment of the complications, if any., Results: A total of 401 patients were evaluable-132 with the internal jugular vein, 136 with the subclavian vein and 133 with the cephalic vein access. No differences were found for the rate of early complications. The US-guided subclavian insertion site had significantly lower failures. Infections occurred in 1, 3, and 3 patients (internal jugular, subclavian, and cephalic access, respectively; p = 0.464), whereas venous thrombosis was observed in 15, 8, and 11 patients, respectively (p = 0.272). Mean cost for purchase, implantation, diagnosis and treatment of complications in each patient was 2,167.85 for subclavian US-guided, 2,335.87 for cephalic, and 2,384.10 for internal jugular access, respectively (p = 0.0001)., Conclusion: US real-time guidance to the subclavian vein resulted in the most cost-effective method of central venous port placement and use.

Advanced enteropancreatic (EP) neuroendocrine tumors (NETs) can be treated with several different therapies, including chemotherapy, biotherapy, and locoregional treatments. Over the last few decades, impressive progress has been made in the biotherapy field. Three main druggable molecular targets have been studied and developed in terms of therapy: somatostatin receptor (sstr), mammalian target of rapamycin (mTOR), and angiogenic factors. In particular, research has moved from the old somatostatin analogs (SSAs), such as octreotide (OCT) and lanreotide (LAN), specifically binding to the sstr-2, to the newer pasireotide (PAS), which presents a wider sstr spectrum. Over the last ten years, several molecular targeted agents (MTAs) have been studied in phase II trials, and very few of them have reached phase III. The mTOR inhibitor everolimus and the multitargeted inhibitor sunitinib have been approved for clinical use by the FDA and EMA in advanced well/moderately-differentiated (WD, MD) progressive pancreatic neuroendocrine tumors (PNETs), on the basis of the positive results of two international large randomized phase III trials vs. placebo. Bevacizumab has been studied in a large US phase III trial vs. interferon (IFN)-alfa2b, and results are pending. In this review, the biological and clinical aspects of MTAs introduced into clinical practice or which are currently in an advanced phase of clinical investigation are addressed.

Background: The incidence of neuroendocrine tumors (NETs) has increased approximately fivefold since the 1980s. A similar increase in the incidence of lung NETs has been reported, but therapy has not been optimized., Methods: This exploratory subanalysis evaluated the efficacy and safety of everolimus plus octreotide long-acting repeatable (LAR) in a cohort of patients with low- to intermediate-grade advanced lung NET from the phase 3, randomized, placebo-controlled RADIANT-2 (RAD001 in Advanced Neuroendocrine Tumors) study. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival, change from baseline in biomarker levels, and safety outcomes., Results: Patients were randomly assigned to everolimus plus octreotide LAR (n 5 33) or placebo plus octreotide LAR (n 5 11). Median PFS was 13.63 months in the everolimus plus octreotide LAR arm compared with 5.59 months in the placebo plus octreotide LAR arm (relative risk for progression: HR, 0.72; 95% CI, 0.31–1.68; P 5 .228). More patients receiving everolimus plus octreotide LAR (67%) experienced minor tumor shrinkage (not partial response as per RECIST [Response Evaluation Criteria in Solid Tumors]) than those receiving placebo plus octreotide LAR (27%). Most frequently reported adverse events (AEs) included stomatitis, rash, diarrhea, and asthenia. This was consistent with the overall RADIANT-2 trial and the safety profile of everolimus., Conclusions: This exploratory subgroup analysis of the RADIANT-2 trial indicates that in patients with advanced lung NET, the addition of everolimus to octreotide LAR improves median PFS by 2.4-fold compared with placebo plus octreotide LAR. These clinically significant observations support the continued evaluation of everolimus treatment regimens in this patient population., Trial Registry: ClinicalTrials.gov; No.: NCT00412061

Among primary liver cancers occurring worldwide, hepatocellular carcinoma (HCC) is the major histological type accounting for 70-85% of all cases. Phase III trials in patients with advanced HCC treated with sorafenib (SO), a multitargeted tyrosine kinase inhibitor, showed significant improvements in both overall and progression-free survival. We report the cases of two elderly patients with advanced HCC who had prolonged stable disease following treatment with SO (400 mg bid). Patient 1 was treated with SO for a period of 16 months until evidence of right sacral metastases was noted. Patient 2 received SO 400 mg bid from January 2009 to October 2009 until radiological evidence of disease progression was noted. Both patients experienced minimal toxicity, suggesting that SO can be safely administered to elderly patients.

Enteropancreatic (EP) neuroendocrine carcinomas (NECs) represent relatively rare and heterogeneous malignancies. They are the most common group among neuroendocrine tumors (NETs). In most cases they are advanced at diagnosis and slow-growing, therefore conditioning a better prognosis compared with non neuroendocrine carcinomas from the same sites. No standard medical therapy exists, except for somatostatin analogs in functioning tumors, and octreotide LAR in functioning or non functioning well differentiated NECs from small bowel. Several systemic therapeutic options exist, including chemotherapy, somatostatin analog, interferon, peptide receptor radionuclide therapy (PRRT), and molecular targeted drugs. Among them some therapies have specific biological tumor targets and can be defined as "biological targeted therapies". This review focuses on the status of EP NECs targeted therapies in the light of recent advances. Somatostatin receptors (SSTRs) are the first therapeutic target detected in EP NECs. Through them SS analogs and PRRT act, producing symptomatic, biochemical, and, to a lesser extent, antiproliferative effects. New SS analogs, covering a higher number of SSTR subtypes, were developed, including pasireotide (SOM230), which controls 25% of carcinoid syndromes resistant to full dose octreotide LAR. Chimeric analogs, which bind SSTR2/SSTR5 and dopamine-2 receptor subtype (D2), are in preclinical phase of development. Among the numerous molecular targeted agents investigated in NETs, mTOR inhibitors and VEGF/VEGFR/PDGFR inhibitors are in most advanced clinical phase of investigation. In particular, everolimus, sunitinib, and bevacizumab are all studied in phase III trials. Both everolimus and sunitinib produced significant survival benefit versus placebo in advanced progressing well-differentiated pancreatic NECs. Sunitinib data have been presented at the last ASCO in June 2010, and everolimus data will be presented at next ESMO in September 2010., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Pancreatic cancer is a malignancy with a very poor prognosis, even when radically resected. In advanced disease chemotherapy has a role in terms of clinical benefit and symptoms palliation, more than survival advantage. Gemcitabine as a single agent is the first-line standard treatment since 1997. Several trials failed to demonstrate a survival advantage of chemotherapy doublets or gemcitabine combined with biological agents versus gemcitabine alone in phase III trials. Erlotinib was the only agent to produce a statistically significant improvement of survival when combined with gemcitabine versus gemcitabine alone. Nevertheless, the clinical application of these literature data remains controversial. However, a meta-analysis showed that combination chemotherapy is superior to gemcitabine alone in terms of survival and clinical benefit in selected subgroups of patients. In unresectable locally advanced disease chemotherapy is active, whereas no high level evidence exists about a possible superiority of chemoradiation. Chemotherapy followed by chemoradiation represents a promising treatment schedule, resulting better than chemotherapy alone in a retrospective analysis. Adjuvant chemotherapy is nowadays a standard treatment, with both 5-FU and gemcitabine resulted superior to observation. Instead adjuvant chemoradiation is not a standard, even though it can be suggested in selected subgroups of patients. In resectable locally advanced disease neoadjuvant therapy is still investigational. Chemoradiation or chemotherapy followed by chemoradiation produced promising results in phase II trials. Possible future gain in terms of survival could come from better neoadjuvant treatments in potentially resectable pancreatic carcinoma. Therefore, this setting should stimulate studies with new drugs and combinations and potential biological predictive factors.

Gastroenteropancreatic endocrine tumours (GEP ETs) represent a relatively rare and heterogeneous group of neoplasms whose therapy can be challenging. The poorly differentiated, fast-growing cases are treated with chemotherapy. In the slow-growing ones, biotherapy is usually performed. Several categories of targeted therapies have been studied for their treatment in vitro and in vivo. A critical review of molecular alterations suggests a rationale for targeting angiogenesis, and the phosphatidylinositol 3 kinase (PI(3)K)/AKT/mammalian target of rapamycin (mTOR) pathway. Accordingly, antiangiogenic agents and mTOR inhibitors are presently the most tested agents in phase II and III studies. Bevacizumab, some multitarget inhibitors, and mTOR inhibitors showed promising results in patients with advanced GEP ETs. A limited activity has been reported for imatinib and epidermal growth factor receptor (EGFR) inhibitors. Combinations of molecular targeted therapies with different sites of action, and somatostatin analogues may be relevant to avoid molecular escape pathways. Future trials should include more homogeneous groups of patients and pay more attention to the subgroup with progressive disease.

Background: Central venous access is extensively used in oncology, though practical information from randomized trials on the most convenient insertion modality and site is unavailable., Methods: Four hundred and three patients eligible for receiving i.v. chemotherapy for solid tumors were randomly assigned to implantation of a single type of port (Bard Port, Bard Inc., Salt Lake City, UT), through a percutaneous landmark access to the internal jugular, a ultrasound (US)-guided access to the subclavian or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. Early and late complications were prospectively recorded until removal of the device, patient's death or ending of the study., Results: Four hundred and one patients (99.9%) were assessable: 132 with the internal jugular, 136 with the subclavian and 133 with the cephalic vein access. The median follow-up was 356.5 days (range 0-1087). No differences were found for early complication rate in the three groups {internal jugular: 0% [95% confidence interval (CI) 0.0% to 2.7%], subclavian: 0% (95% CI 0.0% to 2.7%), cephalic: 1.5% (95% CI 0.1% to 5.3%)}. US-guided subclavian insertion site had significantly lower failures (e.g. failed attempts to place the catheter in agreement with the original arm of randomization, P = 0.001). Infections occurred in one, three and one patients (internal jugular, subclavian and cephalic access, respectively, P = 0.464), whereas venous thrombosis was observed in 15, 8 and 11 patients (P = 0.272)., Conclusions: Central venous insertion modality and sites had no impact on either early or late complication rates, but US-guided subclavian insertion showed the lowest proportion of failures.

Background/aims: Hepatic resection in metastatic disease from colorectal cancer offers the best chance in selected cases for long-term survival. Neoadjuvant chemotherapy (NACT) has been advocated in some cases initially deemed irresectable with few reports of the efficacy of such a strategy and the influence of the response to chemotherapy on the outcome of radical hepatic resection., Methodology: Between December 1995 and May 2005, 88 patients with colorectal liver metastases underwent hepatic resection with curative intent. Twenty-five of these patients, (7 males, 18 females, mean age: 58+/-9 years; range: 40-75 years) deemed as resectable cases at the time of diagnosis were treated with neoadjuvant chemotherapy. A 7-year survival analysis was performed. Chemotherapy included mainly oxaliplatin or irinotecan containing regimens for a median of 6 courses., Results: Fifteen patients (60%) had synchronous and 10 (40%) metachronous metastases. During preoperative chemotherapy tumor regression occurred in 8 cases (32%); stable disease (SD) in a further 10 patients (40%) and progressive disease (PD) developed in 7 cases (28%). The 5-year overall survival for NACT responders was 71% and only 15% for non-responders (p=0.026)., Conclusions: The response to chemotherapy is likely to be a significant prognostic factor affecting overall survival after radical hepatic resection for colorectal metastases.

Purpose: Epidermal growth factor receptor-overexpression reported in colorectal cancer, justifies therapeutic use of EGFR-inhibitors. We have recently conducted a phase II study in 57 patients with EGFR-positive advanced colorectal cancer (ACC) who received gefitinib-FOLFOX6 followed by gefitinib-single agent as maintenance. Main biological objective was to assess sEGFR as surrogate marker of tyrosine kinase inhibition and as predictor of response., Methods: sEGFR, evaluated by quantitative ELISA, was investigated as predictive factor both taking into account the basal value only, and its whole pattern over time. sEGFR was collected at baseline and at every 2-months assessment in 42 cases. Thirty-three patients reported CR/PR as best objective response (BOR), while nine showed SD/PD., Results: Retrospectively, on average, the sEGFR values reported by both responders (CR/PR) and not responders (SD/PD) were already different at baseline (49.4 +/- 6.2 and 42.4 +/- 8.4 ng/ml respectively). This difference was statistically significant (p = 0.042). Although sEGFR trend over time confirmed the basal difference (p = 0.032), this result should be taken with caution, due to the small number of patients reporting EGFR values besides the basal one., Conclusions: Higher sEGFR at baseline was associated to BOR and may be considered a significant predictor of outcome in patients with ACC.

In most cases gastro-enteropancreatic neuroendocrine tumors grow slowly. Interferon-alpha and somatostatin analogs have shown symptomatic, biochemical, and, in a minority of cases, antiproliferative activity. Generally, they are proposed as single-agent therapy. However, based on in vitro and in vivo evidence, the combined use of these drugs was proposed in several non-randomized trials, indicating that there is an additive effect of the combination. Nevertheless, the three randomized trials published so far did not show a statistically significant survival benefit for the combination compared to the same agents alone, even though an advantage for the combination came out in all three studies. On the other hand, data from non-randomized trials would justify the sequential use of the two drugs or the combination after progression on single agent therapy. Therefore, at present the up-front combined use of interferon-alpha and somatostatin analog is not justified, whereas it could be indicated after progression to single-agent therapy. Further larger, international, prospective, randomized, multicentric clinical trials studying homogeneous populations would be necessary to give a final answer, but the rarity and heterogeneity of this malignancy does not assure that it will be possible.

Background/aims: Various percentages of iatrogenic gastroduodenal ulcers during hepatic intra-arterial chemotherapy have been reported in the literature. The aim of this study was to analyze a homogeneous cohort of patients in order to evaluate the evolution and management of this complication., Methodology: We retrospectively reviewed the clinical charts of 80 patients with primary or metastatic liver tumors who received 186 hepatic arterial infusion chemotherapy courses of 5-fluorouracil, cisplatin and mitomycin-C. All of the patients complaining of upper gastrointestinal symptoms during or after hepatic arterial infusion underwent esophagogastroduodenoscopy., Results: Esophagogastroduodenoscopy was performed in 14 patients, all of whom had gastroduodenal ulcers. Two of ten investigated patients were Helicobacter pylori positive. All of the patients were treated with a proton pump inhibitor and five also received major analgesics. All of the ulcers healed without complications. Six patients did not continue with hepatic arterial infusion for reasons other than ulcers. Eight patients received a subsequent hepatic intra-arterial chemotherapy course, five despite the persistence of an active ulcer., Conclusions: Iatrogenic gastroduodenal ulcers are probably due to ischemia and the direct toxicity of the anticancer agents. They are Helicobacter pylori independent and do not represent an absolute contraindication for the continuation of hepatic intra-arterial chemotherapy.