Activity and safety of a prolonged daily schedule of zoledronic acid in a patient with bone metastases from urothelial carcinoma

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Risk factors for pancreas and lung neuroendocrine neoplasms: a case-control study.

Neuroendocrine neoplasia (NEN) has been displaying an incremental trend along the last two decades. This phenomenon is poorly understood, and little information is available on risk factor for neuroendocrine neoplasia development. Aim of this work is to elucidate the role of potentially modifiable risk factors for pancreatic and pulmonary NEN. We conducted a case-control study on 184 patients with NEN (100 pancreas and 84 lung) and 248 controls. The structured questionnaire included 84 queries on socio-demographic, behavioral, dietary and clinical information. Increased risk was associated with history of cancer ("other tumor", lung OR = 7.18; 95% CI: 2.55-20.20 and pancreas OR = 5.88; 95% CI: 2.43-14.22; "family history of tumor", lung OR = 2.66; 95% CI: 1.53-4.64 and pancreas OR = 1.94; 95% CI: 1.19-3.17; "family history of lung tumor", lung OR = 2.56; 95% CI: 1.05-6.24 and pancreas OR = 2.60; 95% CI: 1.13-5.95). Type 2 diabetes mellitus associated with an increased risk of pancreatic NEN (OR = 3.01; 95% CI: 1.15-7.89). Besides site-specific risk factors, there is a significant link between neuroendocrine neoplasia and cancer in general, pointing to a shared cancer predisposition

A classification prognostic score to predict OS in stage IV well-differentiated neuroendocrine tumors

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

Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors

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\ua0years) with advanced PNETs were treated with everolimus for 653\ua0months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD\ua0 64\ua03000\ua0mg (Group A; n\ua0=\ua068) and CD\ua0>\ua03000\ua0mg (Group B; n\ua0=\ua048). 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\ua0months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0-76.7; P\ua0<\ua00.0001). Patients who maintained a DI higher than 9\ua0mg/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\ua0mg despite delays or temporary interruptions

Risk Factors for Disease Progression in Advanced Jejunoileal Neuroendocrine Tumors.

BACKGROUND: Knowledge of clinical course in advanced jejunoileal neuroendocrine tumors (NETs) is poor. Aim: To investigate progression-free survival (PFS), overall survival (OS), and possible predictors for disease progression (DP) in advanced jejunoileal NETs. PATIENTS AND METHODS: We carried out a multicenter, retrospective analysis of incoming patients with sporadic advanced jejunoileal NETs. PFS and OS were assessed by Kaplan-Meier analysis. Risk factors for progression were analyzed by the Cox proportional hazards method. RESULTS: Of the 114 patients enrolled, 46.5% had functioning tumors, 93.9% had stage IV disease, and 57.3 and 42.7% were G1 and G2 tumors, respectively. During a median follow-up of 48 months (interquartile range 29-84 months), DP occurred in 61.4% of patients, after 19 months (interquartile range 10-41 months) from diagnosis. Median PFS was 36 months. The 2-year and 5-year PFS were 59 and 33%, respectively, while 5-year OS was 77.5%. Ki67 was the sole strong independent risk factor for unfavorable outcome according to multivariate analysis, being significantly associated with both PFS and OS. CONCLUSIONS: DP occurred in the majority of patients with advanced jejunoileal NETs, with median PFS being 36 months. Ki67 was a significant predictor of DP and should be considered in determining appropriate treatments and planning follow-up for these patients

Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor

PURPOSE: To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment. METHODS: A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety. RESULTS: Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events. CONCLUSIONS: HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials

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

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

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

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