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Although combination therapy is not recommended in patients with gastro–entero–pancreatic (GEP) neuroendocrine tumors (NETs), this strategy is widely used in clinical practice. This network meta-analysis of randomized trials evaluates targeted therapies and somatostatin analogues in GEP-advanced NETs, either alone or in combination, comparing the efficacy of different, single or combined treatment strategies in terms of progression-free survival (PFS). Interventions were grouped as analogs, everolimus, everolimus plus SSAs, sunitinib and placebo. In a secondary analysis, we also assessed the efficacy of individual-specific pharmacological treatments vs placebo or each other. From 83 studies identified, 8 randomized controlled trials were selected, with a total of 1849 patients with either functioning or non-functioning NETs. The analysis confirmed the superiority of all treatments over placebo (HR ranging from 0.34, 95% CI: 0.24–0.37 with the combination of everolimus plus SSAs to 0.42, 0.31–0.57 with the analogs; moderate quality of evidence). On ranking analysis, the combination of everolimus plus SSA (P score = 0.86) and then everolimus alone (P score = 0.65) ranked highest in increasing PFS. On comparative evaluation of different interventions, pasireotide (P score = 0.96) and everolimus + octreotide (P score = 0.82) ranked as the best pharmacological treatment options. Our findings support the use of combination therapy in the treatment of functioning and non-functioning GEP NETs. The role of pasireotide should be explored in selected subgroups of patients. Lastly, the combination of everolimus and octreotide appears promising and should be more widely considered in clinical practice.

Pheochromocytomas and paragangliomas (PPGLs) can metastasize in approximately 15–20% of cases. This review discusses the available evidence on the biology and treatment of metastatic PPGLs. Chemotherapy is the first-line treatment option for this evolving and symptomatic disease. In patients with high MIBG uptake and positive PETGa-68, radiometabolic treatment may be considered. The efficacy of sunitinib has been shown in observational studies, and pembrolizumab has been evaluated in phase II clinical studies, while other agents investigated in this setting are anti-angiogenic drugs cabozantinib, dovitinib, axitinib and lenvatinib. As these agents' efficacy and safety data, alone or in combination, are scant and based on few treated patients, enrollment in clinical trials is mandatory. Future therapeutic options may be represented by DNA repair system inhibitors (such as olaparib), HIF2 inhibitors and immunotherapy.

To determine whether a red clover preparation plus dietary intervention administered to premenopausal women with breast cancer (BC), improves menopausal symptoms due to anti-oestrogen treatment, and hence promotes compliance with tamoxifen, prevents weight gain and is safe. Surgically-treated premenopausal women with oestrogen receptor (ER) positive disease taking tamoxifen were recruited to a prospective double-blind randomized trial (NCT03844685). The red clover group (N = 42) received one oral tablet/day (Promensil® Forte) containing 80 mg red clover extract for 24 months. The placebo group (N = 39) received one oral tablet/day without active ingredient. All women were encouraged to follow a Mediterranean-type diet and keep active. Outcomes were Menopausal Rating Score (MRS), body mass index (BMI), waist and hip girth, insulin resistance, and levels of cholesterol, triglycerides, and sex hormones. As safety indicators, endometrial thickness, breast density, and effects of patient serum on ER-positive BC cell lines were investigated. MRS reduced significantly (p

TPS4167 Background: Well-differentiated (WD) NETs are a group of rare neoplasms with limited therapeutic options. New combinations of somatostatin analogs (SSAs) and investigational drugs are warranted to improve clinical outcomes. Cabozantinib (CAB) is an orally administered inhibitor of multiple tyrosine kinases, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), with a pivotal role in NET pathogenesis. The biological rationale of the synergistic effects of CAB plus SSAs lies in the concomitant modulation of the RAS/MAPK and PI3K/Akt/mTOR pathways both at the level of cancer cells and tumor stroma, leading to enhanced anti-proliferative and anti-angiogenic effects. CAB exhibited encouraging activity in a recent phase II trial of patients with progressive carcinoids and pancreatic (p)NETs (Chan JA et al. JCO 2017; 35:4_suppl, 228-228). The LOLA trial is the first prospective phase II study aiming to assess the safety and activity of CAB in combination with lanreotide (LAN) in WD NETs of GEP, thoracic and of unknown origin. Clinical trial information: NCT04427787. Methods: This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥10%; positive 68Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids. In the stage I, the primary objective is to find the optimal dose of CAB in combination with LAN and to evaluate the safety of the combination (defined as the percentage of patients experiencing grade 3-5 toxicities according to NCI-CTCAE v5.0). Starting dose of CAB is 60 mg/day continuously, plus LAN 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST v1.1. The useful antitumor activity to be detected is fixed in ORR > 20%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of IHC expression of c-MET, AXL and VEGFR2, with the aim to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop out rate of 5%, the maximum number of enrolled patients will be 69. Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of CAB plus LAN in a group of NET patients with relatively aggressive disease and limited therapeutic options, for whom optimal treatment sequencing is not yet defined. Clinical trial information: NCT04427787.

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.