No abstract

Background: Hyperactivation of mTOR pathway and angiogenesis have been implicated in the pathogenesis of neuroendocrine tumors (NETs). Everolimus, an oral inhibitor of mTOR, and sunitinib, an antiangiogenic drug, are effective targeted therapies approved to treat locally advanced/metastatic pancreatic neuroendocrine tumors (pNETs). Most pNETs are sporadic and mutations in genes involved directly or indirectly in mTOR pathway regulation have been implicated, including somatic mutation in MEN1 in 44% of cases. About 10% of pNETs can be part of hereditary syndromes, e.g., multiple endocrine neoplasia type 1 (MEN1) and Von-Hippel Lindau (VHL), and these patients are underrepresented in pivotal phase III trials.We hypothesized that everolimus would be particularly effective in patients with MEN1-associated pNETs. Likewise, we inferred that sunitinib would also be beneficial to patients with VHL-associated pNETs. Methods:We conducted a multicenter retrospective and comparative study to assess the efficacy of everolimus and/or sunitinib in a cohort of patients with advanced pNETs with or without known MEN1 or VHL syndrome. The evaluation of the germline mutational status of VHL and MEN1 genes was retrospectively collected from the medical records. The primary endpoints were progression free survival (PFS) and time to treatment failure (TTF) of patients who received at least one month of sunitinib or everolimus in monotherapy. Results: Thirty-three patients were identified from September 2009 to April 2018. Most were male 60.6%.Median Ki67 was 9%, liver metastases were present in 97%. The majority of tumors were non-functioning. Thirty-one patients received everolimus, of them 8 patients had germline mutations (6 in MEN1 and 2 in VHL genes). Nine patients received sunitinib, of them 3 had germline mutation (2 in MEN1 and 1 in VHL genes). In a median follow up of 26 months, among everolimus-treated patients, mTTF and mPFS were numerically superior in patients with germline mutations compared with those with sporadic pNETs (mTTF: 16.1 vs. 9.9 months, P=0.888; mPFS: 33.1 vs. 12.3 months, P=0.383). The disease control rate with everolimus was numerically higher in favor of germline mutated tumors compared to sporadic ones (87.5% vs. 68.4%). Sunitinib was used by 1 patient with VHL syndrome, achieving a PFS of 17.6 months.In the subgroup of sporadic pNETs, sunitinib was used by 6 patients reaching a mPFS of 18 months (range, 5-25 months), predominantly in second line. Conclusions: Our study suggests that everolimus may offer a prolonged tumor control in pNETS with germline mutations (MEN1 or VHL) compared to sporadic ones. The small number of patients and the retrospective nature of this study precludes any definitive conclusions.

The background to this study was that factors associated with carcinoid heart disease (CHD) and its impacts on overall survival (OS) are scantly investigated in patients (pts) with neuroendocrine tumors (NETs). In terms of materials and methods, a retrospective multicenter cohort study was conducted of factors associated with CHD in advanced NET pts with carcinoid syndrome (CS) and/or elevated urinary 5-hidroxyindole acetic acid (u5HIAA). CHD was defined as at least moderate right valve alterations. The results were the following: Among the 139 subjects included, the majority had a midgut NET (54.2%), 81.3% had CS, and 93% received somatostatin analogues. In a median follow-up of 39 months, 48 (34.5%) pts developed CHD, with a higher frequency in pts treated in public (77.2%) versus private settings (22.9%). In a multivariate logistic regression, unknown primary or colorectal NETs (Odds Ratio (OR) 4.35; p = 0.002), at least 50% liver involvement (OR 3.45; p = 0.005), and being treated in public settings (OR 4.76; p = 0.001) were associated with CHD. In a Cox multivariate regression, bone metastases (Hazard Ratio {HR} 2.8; p = 0.031), CHD (HR 2.63; p = 0.038), and a resection of the primary tumor (HR 0.33; p = 0.026) influenced the risk of death. The conclusions were the following: The incidence of CHD was higher in pts with a high hepatic tumor burden and in those treated in a public system. Delayed diagnosis and limited access to effective therapies negatively affected the lives of NET patients.

<b><i>Introduction:</i></b> The incidence of infections is poorly studied in patients with neuroendocrine tumors (NET) treated with everolimus outside of clinical trials. We aimed to evaluate the frequency of and risk factors for opportunistic infections (Opl) or any serious infection in eligible patients. <b><i>Methods:</i></b> This was a retrospective multicenter study of a Latin American cohort of consecutive patients with advanced NET treated with everolimus. Duration of everolimus, comorbidities, Charlson comorbidity score, type of prior treatment, institution, and concurrent immunosuppressive conditions were tested for possible associations with serious (grade 3–5) infections in univariate and multivariable logistic regression models. <b><i>Results:</i></b> One hundred eleven patients from 5 centers were included. The median duration of everolimus was 8.9 months. After a median follow-up of 32.9 months, 34 patients (30.6%; 95% CI 22.2–40.1) experienced infections of any grade, with 24 (21.6%; 95% CI 14.8–30.4) having a serious infection and 7 (6.3%; 95% CI 2.6–12.6) having at least 1 OpI (<i>Candida</i> sp., <i>Toxoplasma gondi</i>, <i>Pneumocystis</i> sp., <i>Herpes</i> sp., and <i>Cryptococcus</i> sp.). Four patients (3.6%) died from infections, but only 2 deaths (1.8%) were deemed to be related to everolimus. The multivariable analysis identified everolimus duration (every 6-month increase; OR = 1.28; 95% CI 1.02–1.60; <i>p</i> = 0.03) as an independent risk factor for serious infection. <b><i>Conclusion:</i></b> Infections are more frequent in NET patients using everolimus than previously reported in clinical trials. Patients on everolimus should be closely monitored for infections, especially those receiving it for several months.