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The prognostic role of diabetes mellitus (DM) in advanced enteropancreatic neuroendocrine tumors (NETs) is unclear. Progression free survival (PFS) was assessed in post-hoc analyses of the 96-week, phase III, double-blind, placebo-controlled CLARINET study of lanreotide 120 mg in patients with advanced non-functional enteropancreatic NETs with DM (with/without metformin) and without DM. Of 204 patients, there were 79 with DM (lanreotide, n = 42 {metformin, n = 14}; placebo, n = 37 {metformin, n = 10}) and 125 without DM (lanreotide, n = 59; placebo, n = 66). Median PFS was 96.0 and 98.0 weeks with and without DM, respectively (hazard ratio 1.20 {95% confidence interval 0.79 to 1.82}; p = 0.380). No difference in PFS was observed in lanreotide-treated patients with/without DM ( p = 0.8476). In the placebo group, median PFS was numerically shorter with versus without DM ( p = 0.052) and was significantly longer in patients with DM and metformin (85.7 weeks) versus without metformin (38.7 weeks; p = 0.009). Multivariable Cox analyses showed that DM at baseline was not associated with PFS ( p = 0.079); lanreotide was significantly associated with lower disease progression risk ( p = 0.017). Lanreotide efficacy was confirmed in patients with advanced enteropancreatic NETs, regardless of diabetic status; DM was not a negative prognostic factor. A potential antitumor effect of metformin was observed in patients receiving placebo.

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.)

Objective: The aim of the study was to assess the impact of systemic markers of inflammation on the outcomes in patients with neuroendocrine tumors (NETs) treated with everolimus or placebo (as measured by baseline neutrophil-to-lymphocyte ratio [NLR] and lymphocyte-to-monocyte ratio [LMR])., Methods: Patient data (gastrointestinal, pancreatic, and lung NETs) from 2 large phase 3 studies, RADIANT-3 (n = 410) and RADIANT-4 (n = 302), were pooled and analyzed. The primary end point was centrally assessed progression-free survival (PFS) as estimated by the Kaplan-Meier method., Results: In the pooled population, elevated LMR (median PFS, 11.1 months; 95% confidence interval, 9.3-13.7; hazard ratio, 0.69; P < 0.001) and reduced NLR (median PFS, 10.8 months; 95% confidence interval, 9.2-11.7; hazard ratio, 0.75; P = 0.0060) correlated with longer PFS among all patients. These markers were also found to be prognostic in the everolimus- and placebo-treated subgroups., Conclusions: Data from this study suggest that LMR and NLR are robust prognostic markers for NETs and could potentially be used to identify patients who may receive or are receiving the most benefit from targeted therapies. As both are derived from a complete blood count, they can be routinely used in clinical practice, providing valuable information to clinicians and patients alike., Competing Interests: D.L.C. reports personal fees and nonfinancial support from Novartis and Ipsen and grants from Merck KGaA, outside the submitted work. J.C.Y. reports personal fees from Novartis, Ipsen, Mallinckrodt, Tarveda, Crinetics, Hutchison Medi, Chiasma, Exelixis, and Nektar, outside the submitted work. F.H. was an employee of Novartis (during the time of this research). A.R. is an employee of Novartis. J.S. reports personal fees from Ipsen, Lexicon, and Novartis, outside the submitted work. M.P. reports honoraria for presentations/advisory boards from Ipsen, Pfizer, Lexicon, and Novartis and research support from former institutions—Charité, Ipsen, and Novartis. S.S. reports others from Novartis during the conduct of the study and personal fees from Novartis and Ipsen, outside the submitted work. The other authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT)., Patients and Methods: Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab., Results: A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51-10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07-1.55; P = 0.008] and 1.16 (95% CI 0.99-1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95-1.39; P = 0.147) and 1.1 (95% CI 0.93-1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III., Conclusions: S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths., Clinical Trial Identification: NCT00112918., (Copyright © 2019 European Society for Medical Oncology. All rights reserved.)

Gastroenteropancreatic neuroendocrine tumors (NETs) are a relatively rare group of heterogeneous neoplasms. The most significant advance in therapy of NETs has been the advent of the somatostatin analog octreotide, which represents a cornerstone in their management and dramatically changed the therapeutic landscape. Octreotide long-acting release (LAR) was developed to overcome some of the limitations of octreotide. Several clinical studies, including PROMID and RADIANT-2, have validated the clinical benefits of octreotide LAR in NETs, with tumor shrinkage in about 10% of patients and tumor stabilization in roughly half of cases. While the use of octreotide LAR is well-consolidated in NETs, some open questions remain. These include the use of high-dose octreotide LAR, as there is evidence that higher dose may provide longer disease control, and nonstandard treatment schedules, with administration every 21 days instead of 28 days, as well as their use in combination with targeted agents or peptide receptor radiotherapy in clinical practice. After 3 decades of clinical experience with octreotide LAR, the drug has a well-established safety profile. It is well-tolerated and treatment discontinuations due to adverse events are uncommon. One exception is cholelithiasis, which may increase with longer duration of treatment. According to the literature data, octreotide LAR is currently recommended in both functioning and nonfunctioning advanced NETs. This review summarizes the available clinical data with octreotide LAR and also provides future perspectives on its possible uses in patients with NETs.

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.)

No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n  = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database ( n  = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions ( n  = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS ≥70%; (II) intermediate risk group: 30% ≤ 10-year OS < 70%; (III) poor risk group: 10-year OS <30%. The Harrell C statistic was 0.661 in the training set, and 0.626 and 0.601 in the RARECAREnet and Italian multicentric validation sets, respectively. In conclusion, based on the analysis of three 'field-practice' cohorts collected in different settings, we defined and validated a prognostic score to classify patients into three groups with different long-term prognoses., (© 2018 The authors.)

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.)

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.)

Background: Recently, everolimus was shown to improve median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) tract compared with placebo (HR, 0.48; 95% CI, 0.35-0.67; P <0.00001) in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy) on everolimus activity., Trial Registration: ClinicalTrials.gov identifier: NCT01524783., Patients and Methods: Patients were randomized (2:1) to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy) were analyzed and reported., Results: A total of 302 patients were enrolled, of whom, 163 (54%) had any prior SSA use (mostly for tumor control), 77 (25%) received chemotherapy, and 63 (21%) were previously exposed to radiotherapy. Patients who received everolimus had longer median PFS compared with placebo, regardless of previous SSA (with SSA: 11.1 vs 4.5 months [HR, 0.56 {95% CI, 0.37-0.85}]; without SSA: 9.5 vs 3.7 months [0.57 {0.36-0.89}]), chemotherapy (with chemotherapy: 9.2 vs 2.1 months [0.35 {0.19-0.64}]; without chemotherapy: 11.2 vs 5.4 months [0.60 {0.42-0.86}]), or radiotherapy (with radiotherapy: 9.2 vs 3.0 months [0.47 {0.24-0.94}]; without radiotherapy: 11 vs 5.1 months [0.59 {0.42-0.83}]) exposure. The most frequent drug-related adverse events included stomatitis (59%-65%), fatigue (27%-35%), and diarrhea (24%-34%) among the subgroups., Conclusion: These results suggest that everolimus improves PFS in patients with advanced, progressive lung or GI NET, regardless of prior therapies. Safety findings were consistent with the known safety profile of everolimus in NET., Competing Interests: Disclosure The authors report the following types of declarations of interest: consultant/advisory relationship (C/A), employment (E), honoraria received (H), intellectual property rights/inventor/patent holder (IP), leadership position (L), ownership interest (OI), research funding (RF), speaker’s bureau (SB), and travel and accommodation expenses (TAE). Roberto Buzzoni: Italfarmaco, Novartis, Otsuka (RF); Ipsen, Italfarmaco, Novartis (TAE); Jonathan Strosberg: Novartis (H); Ipsen, Lexicon, Novartis (C/A); Novartis, Pfizer (RF); Bayer, Genentech (SB); Nicola Fazio: Ipsen, Novartis (H); Ipsen, Lexicon, Novartis, Italfarmaco (C/A); Novartis (RF); Ipsen, Novartis (TAE); Simron Singh: Novartis (H, C/A, TAE, RF); Fabian Herbst: Novartis (E, OI); Antonia Ridolfi: Novartis (E); Marianne E Pavel: Ipsen, Lexicon, Novartis, Pfizer (H); Ipsen, Lexicon, Novartis, Pfizer (C/A); Novartis (RF); Ipsen, Novartis (TAE); Edward M Wolin: Celgene, Ipsen, Novartis (C/A); Juan W Valle: Novartis (H, C/A, RF); James C Yao: Ipsen, Lexicon, Novartis (C/A); Novartis (RF); Rodney Pommier: Novartis, Pfizer, Ipsen, Lexicon (C/A); Novartis, Ipsen, Lexicon (TAE). The other authors report no conflicts of interest in this work.

Background: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint., Methods: RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (± 1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783., Findings: Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27-19·35) with everolimus and 9·23 months (5·52-not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55-1·21; log-rank p=0·31)., Interpretation: HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer., Funding: Novartis Pharmaceuticals., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Abnormal expression of succinate dehydrogenase, (SDH), in particular of the B subunit (SDHB), is implicated in the pathogenesis of neuroendocrine tumors. This study evaluates the distribution of SDHB in WHO grading G1 and G2 intestinal, well-differentiated neuroendocrine tumors and corresponding lymph node or liver metastases., Methods: We collected ileal well-differentiated neuroendocrine tumors specimens from consecutive patients with prior primary resection and distant synchronous or metachronous liver metastases. We obtained 195 specimens from primary tumors (n = 106) and metastases (n = 89). The expression (E) of SDHB and the immunostaining intensity (I) were evaluated semiquantitatively and combined into a single score. SDHB score was evaluated in primitive tumor and metastatic specimens., Results: SDHB was found in all tumor cells. Mean SDHB expression was 72.7 % ± 17.1 % in primitive specimens and 27.9 % ± 24.6 % in metastatic specimens (p < 0.0001). SDH intensity was higher in primitive specimens (p < 0.0001). SDHB score was 9-12 in 96 specimens of the primitive group and 2 metastatic specimens (p < 0.0001). None of the analyzed parameters was predictive of overall survival in the primitive subset. In the metastatic subset, loss of SDHB expression, intensity, and score were prognostic factors for survival. Lower expression and intensity of SDHB in metastatic lesions were associated with longer overall survival. When combining SDHB score and Ki-67 % in the metastatic subset, a lower SDHB score was associated with prolonged overall survival, independently from Ki-67 %., Conclusions: SDHB score was different in primitive and metastatic specimens. The combination of SDHB score and Ki-67 % was a stronger predictor of overall survival than Ki-67 % alone. This stratification might help predict survival.

Metformin (MET) has recently emerged as a potentially active agent in cancer prevention and treatment. MET is thought to exert its antitumor effects either via modification of systemic metabolism or through cell-autonomous effects (e.g., activation of AMPK and inhibition of the mTOR pathway). Preliminary findings of the PRIME-NET study suggest that the addition of MET to treatment with everolimus (EVE) and/or somatostatin analogs (SSAs) can provide clinical benefit in diabetic neuroendocrine tumor (NET) patients. In light of this and other retrospective evidence of MET's anticancer activity in NETs, prospective studies are needed. A pilot, single-arm, open-label, prospective study (MetNET-2 trial, NCT02823691) was designed to evaluate the safety of MET in combination with lanreotide in well-differentiated gastrointestinal (WD GI) and lung NETs.

Background: Functional well-differentiated neuroendocrine tumours (NET) with liver metastases represent a therapeutic challenge with few alternative options in guidelines. In these patients, the role of surgical resection of the primary tumour is controversial., Patients and Methods: From a regional registry collecting somatostatin analogue (SSA)-treated tumours from 1979 to 2005, a series of 139 patients presenting with symptomatic, liver-metastatic, well-differentiated NET (G1-G2, mitoses: ≤20, Ki-67: ≤20%) was prospectively collected and retrospectively analysed. Surgery on either the primary tumour or liver metastases was chosen: 1) when low perioperative risk was predictable; 2) in presence of an impending risk of obstruction, bleeding, or perforation; or 3) if liver metastases were suitable of curative or subtotal (>90%) tumour removal. Impact of the most relevant clinico-pathological parameters on survival was studied., Results: Median follow-up was 127 months and median survival was 94 months, with 138 vs. 37 months in resected vs. non-resected primary NET (p < 0.001), respectively. In the univariate analysis, prolonged survival was significantly associated with primary tumour resection (p < 0.001), resection of liver metastases (p = 0.002), site of primary (carcinoid vs. pancreatic, p = 0.018), basal chromogranin-A (CgA) <200 ng/mL (p = 0.001), and absence of diarrhea (p = 0.012). Multivariate analysis showed that primary tumour resection was an independent positive prognostic factor (HR = 3.17; 95% CI: 1.77-5.69, p < 0.001), whereas diarrhea, basal CgA ≥200 ng/mL, and high tumour load were independent negative prognostic factors. Also, in 103 patients with non-resectable liver metastases, primary tumour resection was significantly associated with prolonged survival (median 137 vs. 32 months, p < 0.0001)., Conclusions: Primary tumour resection may improve survival in functional well-differentiated NET with liver metastases., (Copyright © 2016. Published by Elsevier Ltd.)

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., (© 2016 S. Karger AG, Basel.)

Selection criteria and benefit of liver transplantation for hepatic metastases from neuroendocrine tumors (NETs) remain uncertain. Eighty-eight consecutive patients with metastatic NETs eligible for liver transplantation according to Milan-NET criteria were offered transplant (n = 42) versus nontransplant options (n = 46) depending on list dynamics, patient disposition, and age. Tumor burden between groups did not differ. Transplant patients were younger (40.5 vs. 55.5 years; p < 0.001). Long-term outcomes were compared after matching between groups made on multiple Cox models adjusted for propensity score built on logistic models. Survival benefit was the difference in mean survival between transplant versus nontransplant options. No patients were lost or died without recurrence. Median follow-up was 122 months. The transplant group showed a significant advantage over nontransplant strategies at 5 and 10 years in survival (97.2% and 88.8% vs. 50.9% and 22.4%, respectively; p < 0.001) and time-to-progression (13.1% and 13.1% vs. 83.5% and 89%; p < 0.001). After adjustment for propensity score, survival advantage of the transplant group was significant (hazard ratio = 7.4; 95% confidence interval (CI): 2.4-23.0; p = 0.001). Adjusted transplant-related survival benefit was 6.82 months (95% CI: 1.10-12.54; p = 0.019) and 38.43 months (95% CI: 21.41-55.45; p < 0.001) at 5 and 10 years, respectively. Liver transplantation for metastatic NETs under restrictive criteria provides excellent long-term outcome. Transplant-related survival benefit increases over time and maximizes after 10 years., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Well-differentiated bronchial neuroendocrine tumors (B-NETs) are rare. They represent 1-5 % of all lung cancers. The incidence of these neoplasms has risen over the past 30 years and, especially for advanced or metastatic disease, management is complex and requires a multidisciplinary approach. Treatment with somatostatin analogs (SSAs) is the most important first-line therapy, in particular in well-differentiated NETs with high somatostatin type receptor (SSTR) expression. In these tumors, the role of mammalian target of rapamycin (m-TOR) inhibitors and the potential utility of other target therapies remain unclear while chemotherapy represents the gold standard treatment only for aggressive forms with low SSTR expression. Peptide receptor radionuclide therapy (PRRT) is an emerging treatment modality for advanced NETs. There are many cumulative evidences about the effectiveness and tolerability of this therapeutic approach, especially in gastro-entero-pancreatic (GEP)-NETs. For B-NETs, scientific research is moving more slowly. Here, we performed a review in order to evaluate the efficacy and toxicity of PRRT with a focus on patients with inoperable or metastatic well-differentiated B-NETs.

Introduction: Small intestinal (SI) neuroendocrine tumors (NETs) are relatively rare tumors. Due to the lack of symptom or specific symptoms, SI-NETs are often diagnosed at an advanced stage, making therapy challenging. The management of patients with advanced stage SI-NETS requires a multidisciplinary approach that combines surgical and medical treatment including novel targeted molecular therapies., Areas Covered: This article summarizes current strategies for the medical treatment of SI-NETS. Expert commentary: The treatment plan of advanced-stage SI-NETs should be tailored in a case-by-case manner with the adoption of a multidisciplinary approach that combines different treatment options, including biological targeted therapies. In particular, we believe that the identification of the optimal treatment sequence(s), correct treatment timing and the selection of patients eligible to different treatments need specific investigation in controlled clinical trials.

In the last five years, everolimus has demonstrated efficacy in the treatment of neuroendocrine tumors (NETs) of different origins; its efficacy and safety were explored in the RADIANT trials, the last of which (RADIANT-4) has been recently published (December 2015). Overall, evidence collected from the RADIANT studies holds promise to change clinical practice for the treatment of NETs.In this paper, we comment on the role of everolimus within the therapeutic algorithm for NETs treatment, based on the systematic analysis of the RADIANT trials and our experience., Competing Interests: There is no conflict of interest.

Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.

A bidirectional relationship seems to exist between diabetes mellitus and development of pancreatic tumors. Metformin, the most widely used drug in the treatment of Type 2 diabetes mellitus, has recently emerged as a potentially active agent in cancer chemoprevention and treatment. In this article, we discuss the potential correlation between glycemic status, administration of antiglycemic treatments, such as metformin or insulin, and prognosis of pancreatic neuroendocrine tumors patients treated with everolimus and octreotide, on the basis of existing evidence and our experience.

An estimated 20% to 30% of all neuroendocrine tumours originate in the bronchial tree and lungs. According to the 2015 World Health Organization categorization, these tumours are separated into four subtypes characterized by increasing biological aggressiveness: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma and small-cell carcinoma. Although typical and atypical lung carcinoids account for less than 1-5% of all pulmonary malignancies, the incidence of these neoplasms has risen significantly in recent decades. Surgery is the treatment of choice for loco-regional disease but for advanced lung carcinoids there is no recognized standard of care and successful management requires a multidisciplinary approach. The aim of this review is to provide a useful guide for the clinical management of lung carcinoids., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

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.)

Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors. The present review discusses current therapeutic strategies for the treatment of gastro-entero-pancreatic NEN. Several systemic options are currently available, including medical systemic chemotherapy, biological drugs, somatostatin analogs and peptide receptor radionuclide therapy. The carcinoid syndrome can be adequately controlled with somatostatin analogs; chemotherapy has shown positive outcomes in poor prognosis patients, and peptide receptor radionuclide therapy is a promising treatment based on the use of radioisotopes for advanced disease expressing somatostatin receptors. Targeted therapies, such as multikinase inhibitors and monoclonal antibodies are also recommended or under evaluation for the treatment of advanced NENs, but some critical issues in clinical practice remain unresolved. Depending upon the development of the disease, a multimodal approach is recommended. The treatment strategy for metastatic patients should be planned by a multidisciplinary team in order to define the optimal sequence of treatments.

Objectives: The aim of this study was to evaluate the feasibility and tolerability of capecitabine administration according to a specific time schedule, combined with adjuvant radiation therapy, in intermediate-risk to high-risk rectal cancer patients treated with an upfront surgery. The primary endpoint was the rate of grade 3 to 4 diarrhea during chemoradiation (CRT)., Materials and Methods: Stage II and III rectal cancer patients received, after total mesorectal excision, 2 cycles of XELOX regimen (oxaliplatin 130 mg/m(2) on day 1; capecitabine 1000 mg/m(2) bid on day 1 to 14, q21), followed by capecitabine (800 mg/m(2) bid daily; 20% dose at 12:00 AM and 80% dose at 12:00 PM) administered continuously during pelvic radiation (total 50.4 Gy in 28 fractions, 1.8 Gy daily dose between 2:00 and 4:00 PM). Four additional cycles of XELOX were administered after chemoradiotherapy., Results: Fifty-one radically resected rectal cancer patients were enrolled. All, but one, cases were evaluated for safety of CRT. We reported a grade 3 and 4 diarrhea rate of 14% (7 of 50 patients), whereas no grade 3 and 4 leukopenia was observed. Grade 1 and 2 proctitis was observed in 26 (52%) cases, whereas grade 1 and 2 cystitis in 5 (10%) patients. Only 2 cases of grade 3 proctitis and cystitis were reported, respectively. The CRT phase was feasible and was completed by 43 (84%) patients. Three patients developed actinic enteritis 60 days after the end of the radiotherapy program., Conclusions: Capecitabine timetable administration combined with adjuvant radiation therapy of rectal cancer is well tolerated and feasible. Further investigation of this chronomodulated schedule in terms of efficacy is warranted in neoadjuvant setting.

Abnormal PI3K-AKT-mTOR pathway signalling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor-1, have been implicated in the proliferation of pancreatic neuroendocrine tumor (pNET) cells. Everolimus, an mTOR inhibitor, has shown antitumor benefit in pNETs alone and in combination with octreotide LAR in RADIANT-1 and RADIANT-3 studies. Although everolimus-based phase II/III trials have improved progression-free survival for pNET, its use has not impacted on prolonging overall survival. Metformin has recently shown some anti-cancer activity in both in vitro and in vivo studies by its indirect properties to decrease insulin and insulin-like growth factor-1 (IGF-1) levels and by its antitumour effect to promote AMPK activation and consequently inhibition to TSC1-2/mTOR complex. In light of even more retrospective evidence of metformin's anticancer activity, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of metformin in combination with everolimus and octreotide LAR in pancreatic well-differentiated neuroendocrine tumor patients, a single arm, prospective, single center phase II study was designed (MetNET-1 trial, NCT 02294006). Forty-three patients are expected to be evaluated. The study is ongoing, and recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017.

Background: Biliary tract cancer (BTC) is a highly lethal disease for which the best available therapy remains undetermined. The mammalian target of rapamycin (mTOR) pathway is up-regulated in several cancers, including BTC, and preclinical evidence indicates that mTOR inhibition may be effective in the treatment of BTC. We sought to evaluate the activity and tolerability of the mTOR inhibitor RAD001-everolimus-in patients with BTC progressing after prior chemotherapy., Patients and Methods: This was an open-label, single-arm, phase II study (EUDRACT 2008-007152-94) conducted in eight sites in Italy. Patients with locally advanced, metastatic or recurrent BTC progressing despite previous chemotherapy received a daily oral dose of everolimus 10 mg administered continuously in 28-day cycles. The two primary end points were disease control rate (DCR) and objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS) and time-to-progression (TTP)., Results: Thirty-nine patients were enrolled. The DCR was 44.7%, and the ORR was 5.1%. One patient showed a partial response at 2 months and one patient showed a complete response sustained up to 8 months. The median (95% confidence interval) PFS was 3.2 (1.8-4.0) months, and the median OS was 7.7 (5.5-13.2) months. The median TTP was 2.0 (1.7-3.7) months. Most common toxicities were asthenia (43.6%), thrombocytopenia (35.9%), pyrexia (30.8%) and erythema, mainly of mild-to-moderate severity. Two patients required dose reduction due to adverse events., Conclusion: Everolimus demonstrated a favourable toxicity profile and encouraging anti-tumour activity. Further trials are needed to establish the role of everolimus in the treatment of BTC. EUDRACT 2008-007152-94., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [(90)Y]DOTA-TATE and [(177)Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter ((90)Y) and a medium-energy beta/gamma emitter ([(177)Lu) in patients with metastatic NET refractory to conventional therapy., Methods: A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [[(177)Lu]DOTA-TATE (5.55 GBq) and [(90)Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [[(177)Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST., Results: Administration of tandem [(90)Y]DOTA-TATE and [[(177)Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment., Conclusion: The results of our study indicates that combined [(90)Y]DOTA-TATE and [(177)Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach.

Aim: Only few efforts have been taken to investigate the potential existence of disease-specific differences in the safety profile of everolimus. We analyze here the correlation between different patient and tumor characteristics on the safety profile of this molecule. Information on treatment response is also provided., Methods: Consecutive patients with metastatic renal cell carcinoma (mRCC), pancreatic neuroendocrine tumors (pNET) or biliary tract cancer were included in this retrospective study. All patients received everolimus 10 mg/day or 5 mg/day. Clinical assessments were performed every 3 weeks., Results: In total, 98 patients were enrolled: 51 with mRCC, 25 with pNET and 22 with biliary tract cancer. The incidence of toxicities (any grade) was 76% with mRCC, 64% with pNET and 95% with biliary tract cancer. Patients with biliary tract cancer also presented a higher frequency of severe toxicities: 64 versus 18% with mRCC and 32% with pNET. Multivariate analysis disclosed that biliary tract cancer (odds ratio [OR]: 23.8; 95% CI: 6.0-117.8; p < 0.0001) is a predictive factor for the development of toxicities during everolimus treatment. No correlations between liver metastasis and toxicities were identified. Disease control rate (DCR) was 45% in mRCC patients, 96% in pNET and 50% for biliary tract cancer patients. pNET tumors were associated with a higher DCR than the mRCC and biliary tract cancer (OR vs mRCC: 66.7; 95% CI: 6.2-276.5; p = 0.004; OR vs biliary tract cancer: 2.6; 95% CI: 0.5-14.2; p = 0.025)., Conclusion: This study suggests that the safety profile of everolimus is acceptable in patients with either mRCC or pNET. In addition, the onset of toxicities is associated with an improved DCR. In patients with biliary tract cancer, everolimus is safe but associated with a higher incidence of adverse events.

Background: Acute hypersensitivity reactions are adverse events potentially associated with antineoplastic drug infusions. Their occurrence can be particularly relevant in an outpatient environment where time of administration and subsequent observation is limited to a short period of time. In addition, concern about the onset of more severe hypersensitivity reactions can limit subsequent use of crucial drugs., Methods: During a 3-year observational period, we collected a total of 240 infusional acute hypersensitivity reactions out of 56,120 administrations performed, with an overall incidence of 0.4%., Results: In order of frequency, platinum derivatives, taxanes and monoclonal antibodies accounted for the highest incidences. Their relative frequency was: oxaliplatin, 2.5%; carboplatin, 0.4%; paclitaxel, 1.2%; docetaxel, 1.2%; trastuzumab, 1.2%, and rituximab, 1.2%., Conclusions: Since the number of chemotherapeutic agents is steadily increasing, much attention should be paid to such reactions, particularly when several administrations are performed daily, and where management of the potential risk associated with specific drugs is mandatory. Their occurrence represents an unpredictable, unexpected and often hard to manage contingency, and our opinion is that observation and consciousness of this issue are fundamental for its appropriate management. We describe our experience, emphasizing the role of this toxicity and explaining how this awareness allowed us to define some empirical rules to handle acute hypersensitivity reactions.

Oxaliplatin, a platinum analogue employed in the treatment of colorectal cancer and various other neoplasms, is characterized by a broad range of adverse events. Peripheral neuropathy is probably the most peculiar and clinically relevant toxicity associated with its use and can be distinguished into two types: acute and chronic neurotoxicity.We report a case of acute reversible bilateral palpebral ptosis and dyspnea without bronchospasm or laryngospasm which occurred at the end of the third administration of adjuvant oxaliplatin by infusion for stage III colon cancer in a 54-year-old woman. Chlorphenamine and hydrocortisone were administered with fast resolution of dyspnea and slight improvement of ptosis. Complete resolution with no sequelae occurred in one hour. No further recurrence of blepharoptosis was described during the following days. The subsequent cycles were prescribed at reduced dosage without acute complications.

The incidence of neuroendocrine tumors is rising, and this rise is explained by more than just better diagnostic procedures. About 85% of these neoplasms arise in gastrointestinal or pulmonary sites, but cases where the location is more unusual also occur in clinical practice. The tailgut cyst is a rare entity well described in the medical literature, but a neuroendocrine tumor within such a cyst is a very rare event, with about 30 cases described in the literature to date. In this report we present the case of a young woman with this unusual diagnosis. The characteristics of the case differ from most previous case reports in a few respects: the patient was a young rather than middle-aged female; she had a presacral mass with a significant solid component; at diagnosis, there was evidence of a lytic lesion in the coccyx. Despite this particular medical presentation, radical surgery was accomplished. In this disease the greatest risk is local relapse, but adjuvant radiotherapy may compromise the patient's fertility. We therefore opted for strict control only, but this decision might be debatable.

Iodine-131 metaiodobenzylguanidine (I-131 MIBG) has been used for the diagnosis and treatment of malignant pheochromocytomas (PHEO) and paragangliomas (PGL) since 1980's. Despite increasing amount of experience with iodine-131 (I-131) MIBG therapy, many important questions still exist. In this article, we will discuss the current problems learned from clinical experience in diagnosis and therapy of PHEO/PGL with I-131 MIBG, and present a sample case to emphasize the critical aspects for an optimal treatment strategy.

Pheochromocytoma and paraganglioma are rare neuroendocrine tumors. Knowledge about such neoplasms ameliorated in the last 10-15 years with the discovery of increasing number of germ line mutations even in apparently sporadic cases. Seemingly, genetic tests are going to be an integral part of diagnostic procedures. Standard therapies (advanced surgery, radiometabolic therapy, chemotherapy and radiotherapy) have revealed suboptimal results in tumor size reduction and survival. Currently, there is no standard therapeutic protocol and thus some patients end up with overtreatment while others are undertreated. An effective molecular target therapy aiming at permanent control of these highly complex neoplasms should be the aim of future efforts. In clinical setting investigatory trials with multiple drug therapies targeting a variety of different parallel pathways should be available. Successful management requires a multidisciplinary teamwork.

Aims and Background: Anemia prevalence and incidence in chemotherapy-treated patients is high. Erythropoiesis-stimulating agents (ESAs) are frequently employed in the management of chemotherapy-induced anemia. However, other treatments such as red blood transfusion or iron supplementation are normally used. Recent international guidelines raised some concern about ESAs employment with a possible impact in chemotherapy-induced anemia management and changes in clinical practice behavior., Methods: To evaluate opinions about chemotherapy-induced anemia clinical management preference, the Associazione Italiana Oncologia Medica (AIOM) Lombardy section coordinators sent via email a 12-item questionnaire about their knowledge on CIA and usual therapeutic strategies to manage this adverse event to AIOM Lombardy onco-hematologist members., Results: From January 2011 to March 2011, 81 questionnaires were collected with an approximated share of 30%. The survey was completed mainly by oncologists (91%) aged 35-50 years (50%). Chemotherapy-induced anemia was considered to have clinical impact in changing cancer therapeutic strategy by nearly 60% of the respondents. ESAs were administered largely (80%) with concomitant iron supplementation in 52%; 38% jointly used blood transfusion as part of the therapy. Nearly 20% of those who replied correctly employed transferrin saturation levels as a marker to guide iron supplementation. Physician prescribers strictly followed the guidelines to start and stop ESAs even if 14% were negatively influenced by new ASCO recommendations. ESA biosimilars were considered future substitutes of originators in 45% of the cases., Conclusions: Chemotherapy-induced anemia was perceived as an adverse event with a mild impact on clinical practice. ESAs were largely employed, however the number of transfusions and lack of employment of markers of iron depletion suggested that adherence to guidelines could be theoretically met but with some discordances regarding the most appropriate strategies in daily clinical practice.

A 48-year-old man was referred to our hospital with the diagnosis of colon cancer with multiple hepatic metastases. After right hemicolectomy, the rapid progression of liver disease was treated with metronomic capecitabine and bevacizumab according to a study protocol. A gradual regression of metastatic lesions was observed during a 9-month treatment period. After conversion of liver disease to resectability, the histological examination disclosed the complete necrosis of all lesions, with the exception of small neoplastic foci inside a single nodule. The comparison of this type of histological findings with the classic sclero-hyaline pathological response, as well as its importance as indicator of response to antiangiogenic treatment, is discussed.

Primary malignant melanoma (MM) of the uterine cervix is an extremely rare neoplasm, with about 78 cases described in the literature. Since traces of melanocytes in normal cervical epithelium were found in 3.5% of cases primary origin of melanoma at this site cannot be ruled out. It occurs mainly in the sixth decade of life, and it is five time less common than primary vaginal or vulvar MM. Clinical history usually includes abnormal genital bleeding; and physical examination frequently reveals a pigmented, exophytic cervical mass. Diagnosis is confirmed by immuno-histochemical methods and by exclusion of any other primary site of melanoma. Treatment of this condition is not yet standardized, and the overall prognosis is very poor. Diagnostic approaches and therapeutic procedures on primary MM of the uterine cervix are discussed following a review of the literature encompassing more than one century., (© 2011 Elsevier Ireland Ltd. All rights reserved.)

Targeted therapies have improved survival in patients with metastatic renal cell cancer (RCC); however, expert opinion on the optimal therapeutic strategy is divided. This retrospective study evaluates different sequential schemes of targeted therapies in 310 patients with advanced/metastatic RCC who received different systemic agents - sorafenib, sunitinib, bevacizumab, everolimus, temsirolimus and axitinib - alone or in different sequences, until disease progression or intolerable toxicity (median follow-up: 37 months). The median overall survival (OS) was 22 months and the 5-year OS was 23.4%; differential therapeutic schemes were not associated with differences in OS. A worse performance status, no nephrectomy and a poor-risk classification according to the Motzer criteria was associated with a shorter OS. These findings support the use of targeted therapies in the treatment of RCC, even in a large unselected population from a single institution, and suggest that treatment should be tailored to meet individual circumstances and needs.

In order to evaluate the clinical efficacy and the safety profile of molecularly targeted therapies as a palliative approach in elderly populations affected by advanced thoracic neoplasms, we retrospectively studied, in terms of effectiveness and toxicities, a group of pretreated elderly metastatic non-small cell lung cancer (NSCLC) patients admitted to our institution and treated with erlotinib at standard daily/dose. Forty-three patients aged 70 years or older who had previously failed on chemotherapy or radiotherapy were treated with oral Eerlotinib (150 mg/d) until disease progression or unacceptable toxicity. Clinical data, pathological types, potential prognostic factors, efficacy and toxicity of erlotinib were included in this analysis. In our series we observed: objective responses in six patients (14%) and stable disease in 15 (35%). Skin rash was the most common side effect (67%). Grade 3-4 adverse events were observed in 16 cases (37%). The median overall survival and the median progression-free survival were 8.4 months (CI 95%: 0.7-43.6) and 3 months (CI 95%: 0.4-28.4), respectively. Patients with adenocarcinoma achieved the best disease control rate (p = 0.027), while not/former smokers showed a better response (p = 0.069). In our experience the use of erlotinib after chemotherapy failure in an unselected elderly population affected by NSCLC showed moderate efficacy and a moderate safety profile. However, erlotinib represents a valid option in this setting, but other factors such as biological information, comorbidities and concomitant medications need to be carefully take into consideration in this particular subset of cancer patients.

Although major progress has been achieved in the treatment of metastatic colorectal cancer with the employment of biological antiangiogenic agents, several questions remain open for discussion regarding the use of this therapy in elderly patients with metastatic colorectal cancer. In Western countries, the total number of elderly patients with colorectal cancer is expected to increase in the future. As adverse physical or socioeconomic conditions are more common in the elderly, an assessment of the patient's suitability for this therapy should be performed before a treatment decision is made. Most patients in clinical trials of the antiangiogenic drug bevacizumab were aged <65 years and thus the efficacy and tolerability of this agent in older patients has been less well explored. However, this article shows that older and younger patients with metastatic colorectal cancer appeared to derive similar survival benefit from bevacizumab treatment. Elderly patients were also found to have significant prolongation of median progression-free survival with the addition of bevacizumab to their treatment, with a similar magnitude of improvement in this outcome being observed in younger and older patients. It should be emphasized that the patients included in the studies discussed in this article were eligible for clinical trials and therefore may not be representative of a more general elderly population. Careful selection of patients and monitoring of treatment effects are required to optimize use of the antiangiogenic agent bevacizumab in older patients.

Neuroendocrine tumors of the lung involve an heterogeneous group of tumors representing a wide range of histological variants, from well-differentiated typical carcinoid (TC) tumors to poorly differentiated small cell carcinomas. The epidemiology, clinical outcome, and management of these neoplasms differ significantly from other lung malignancies. The main aim of this report consists in describing the single Center experience of the Istituto Nazionale Tumori of Milan on neuroendocrine lung tumors, with an emphasis on bronchopulmonary carcinoid subtypes. From 1986 to 2009, 91 cases of carcinoid tumors were diagnosed; these were divided in two series, according to typical (66 patients) or atypical [25] histotypes. These two groups were compared in relation to various features, including pathologic classification, clinical behavior, treatment modalities and long-term survival. At the moment of diagnosis 11 patients had locally advanced/metastatic disease, while 80 patients showed non metastatic disease. The comparative analysis between typical and atypical series disclosed significant differences in terms of long-term survival; in fact, 5-year and 10-year survival rates were 98 % and 94 % for the first carcinoid series versus 76 % and 18 % for the atypical series, respectively (p<0.001). The median overall survival (OS) was 76 months (range 3-182) for atypical carcinoids and has not yet been reached for TCs patients.

Drug-induced acute thrombocytopenia is an extremely rare side effect that may occur immediately after oxaliplatin infusion. This potentially fatal reaction is immune mediated and can be anticipated by mild hemorrhagic signs during previous administrations. This is the first report of acute thrombocytopenia occurring during adjuvant treatment of colorectal cancer with oxaliplatin. Clinicians should be aware of this adverse event in order to prevent possible serious consequences and stop further oxaliplatin administration.

Aims and Background: Carcinoids are infrequent neoplasms arising from neuroendocrine cells. Due to blurred symptoms and the presence of equivocal diagnostic findings, these tumors are sometimes misdiagnosed. Therefore, increased rates of false neuroendocrine tumors represent an emerging problem in clinical practice. Our aim is to alert clinicians on this matter by supplying them with useful warnings., Methods: In the specialized neuroendocrine tumor study Center Centro di Riferimento per lo Studio e la Cura dei Carcinoidi e dei Tumori Neuroendocrini (Ce.Ri.Ca), some patients highly suspected to have a neuroendocrine tumor have been recognized as having false neuroendocrine tumors. The related clinical and instrumental findings leading to a previous wrong neuroendocrine tumor diagnosis are reported., Results: From July 2006 to December 2008, 88 consecutive cases of neuroendocrine tumors (Nets) were referred at Ce.Ri.Ca. In the former group, 8 cases of false Nets were discovered while in the remaining 80 cases a correct Net diagnosis was carried out. Watchful differential diagnoses and skill appraisal of laboratory investigations resulted in: chronic atrophic gastritis with enterochromaffin-like cell hyperplasia (4 cases), estrogen-deprivation syndrome (1), hypochondriac disorder (1), metabolic syndrome (1), and sarcoidosis (1)., Conclusions: Neuroendocrine tumors are still relatively known clinical entities. To discriminate false neuroendocrine tumors from neuroendocrine tumors requires a good expertise and a large daily practice with the disease. Good knowledge and skillfulness in identifying biochemical alterations and false radiological positive results could avoid both patient inconvenience and very expensive workup. The importance of a multidisciplinary approach in specialized centers is emphasized.

Purpose: This study evaluated the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine in pre-treated metastatic colorectal cancer patients., Methods: Five dose level combinations with irinotecan (from 180 to 240 mg/m(2), day 1, q21), capecitabine (1,500-2,000 mg/m(2) per day, days 2-15, q21) and erlotinib (50-150 mg per day, continuously) were planned. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity., Results: Twenty-one patients were treated. In the first cohort, no DLT was reported, in the second: one DLT (G4 neutropenic fever associated with G3 cutaneous rash and mucositis); in the third dose level: two DLT (G3 diarrhea and G4 neutropenic fever). To confirm these results, other six patients were additionally included and no DLT was observed., Conclusions: The results documented that erlotinib at the dose of 100 mg per day, irinotecan 180 mg/m(2) and capecitabine 1,500 mg/m(2) per day for 14 days has an acceptable safety profile and appears suitable for further phase II studies.

A rare variant of malignant melanoma (MM) of the uterine cervix that mimics a malignant peripheral nerve sheath tumor (MPNST) is described. A 43-year-old white woman was admitted to the hospital complaining of genital discharge and vaginal bleeding. Neoadjuvant chemotherapy and total abdominal hysterectomy and bilateral salpingo-ovariectomy plus pelvic lymphadenectomy were performed, and the diagnosis was MPNST, FIGO IIB. Pathological examination showed a diffuse proliferation of amelanotic spindle cells and large, highly atypical, frequently multinucleated, bizarre, and S100-, HMB-45-, vimentin-positive cells. The patient remained disease-free for 43 months, when an abdominal computed tomographic scan showed local polypoid vaginal lesions, with histological features of typical MM. A pathological review was obtained in our institution by a gynecological pathologist, who defined the primary neoplasm in the cervix as an MM, with a pattern of growth histologically simulating an MPNST, metastatic to the vagina. To our knowledge, this is the first report in literature of MM of the uterine cervix resembling MPNST. Despite its rarity, this variant of MM should be considered when a diagnosis of cervix MPNST is made. The histological and immunohistochemical features of these different entities should be considered in the differential diagnosis.