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Background: Vasoactive intestinal peptide (VIP)-secreting tumors (VIPomas) are digestive neuroendocrine tumors in which the hormonal secretion is life-threatening. Biological confirmation is obtained by demonstrating an elevation in plasma VIP, usually using radioimmunoassay (RIA). In some cases, analytical interference is suspected. We developed 3 different techniques to detect interference in VIP RIA. Methods: Three techniques were used: RIA after Sephadex column chromatography separation, RIA after polyethylene glycol precipitation, and 125I-labeled VIP binding test. We included patients with suspicion of false positive VIP (FPV) elevation. We then compared results with those of a group of "real," proven VIPoma (RV). Results: A total of 15 patients with FPV elevation and 9 RV patients were included. Interference was detected in all FPV patients vs none in RV. Clinical and biochemical parameters did not differ between FPV and RV patients, but VIP concentration in RIA was significantly higher in FPV patients than in RV patients (228â pmol/L vs 66â pmol/L, P = .038). Using a 125I-labeled VIP binding test, median proportion of radioactivity in the pellet was significantly higher in FPV than in RV patients (53% vs 13%, P < .0001). A 20.5% threshold presented excellent performances (sensitivity 100% [79.6-100], specificity 100% [70.1-100]). Conclusion: We developed 3 different laboratory techniques to reveal interference in RIA VIP assays. The diagnostic performance of all 3 was excellent. These techniques must be employed in cases of discordance between VIP elevation and clinical presentation.
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The outcome following surgery for patients with primary lung neuroendocrine tumors at metastatic stage remains poorly characterized. We conducted a retrospective national study including patients with metastatic lung neuroendocrine tumors at diagnosis. We performed a safety study to evaluate major morbidity and mortality of surgical resection of the primary tumor and compared patients in the operative to the nonoperative group. A total of 155 patients were included: 41 in the operative group and 114 in the nonoperative group, median age was 64 years. Metastases were mainly located in the liver (74.2%) and the bone (49.7%). The primary endpoint was met as the rate of major complications was 4.9% and there was no postoperative mortality. In the operative group 42.5% of patients had improvement of their pulmonary symptoms versus 14.4% in the nonoperative group. The median overall survival was not reached in the operative group and was 4.3 years (95% CI [3.5;4.9]) in the nonoperative group (univariate analysis, HR = 0.42 95% CI [0.23-0.77], p = .002). After multivariate analysis, only an ECOG-PS ≥1 (vs. 0, HR = 2.44, 95% CI [1.46;4.07], p = .001) and >1 metastatic site (vs. 1; HR = 1.83, 95% CI [1.06;3.16], p = .030) remained significantly associated with overall survival. The resection of the primary tumor was not significantly associated with overall survival (HR = 0.63, 95% CI [0.32;1.24], p = .183). In conclusion, surgery of primary lung neuroendocrine tumors at metastatic stage is a safe option that should be considered in selected patients in order to improve symptoms with a view to improving their quality of life. Larger studies are warranted to evaluate the impact of surgery on survival.
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Carcinoid heart disease (CHD) is the main complication of carcinoid syndrome (CS) associated with metastatic small intestine neuroendocrine tumours (NETs). The pathophysiology of CHD is partly understood but vasoactive hormones secreted by NETs, especially serotonin, play a major role, leading to the formation of fibrous plaques. These plaque-like deposits involve the right side of the heart in >90% of cases, particularly the tricuspid and pulmonary valves, which become thickened, retracted and immobile, resulting in regurgitation or stenosis. CHD represents a major diagnostic and therapeutic challenge for patients with NET and CS and is associated with increased risk of morbidity and mortality. CHD often occurs 2-5 years after the diagnosis of metastatic NET, but diagnosis of CHD can be delayed as patients are often asymptomatic for a long time despite severe heart valve involvement. Circulating biomarkers (5HIAA, NT-proBNP) are relevant tools but transthoracic echocardiography is the key examination for diagnosis and follow-up of CHD. However, there is no consensus on the optimal indications and frequency of TTE and biomarker dosing regarding screening and diagnosis. Treatment of CHD is complex and requires a multidisciplinary approach. It relies on antitumour treatment, control of CS and surgical valve replacement in cases of severe CHD. However, cardiac surgery is associated with a high risk of mortality, notably due to perioperative carcinoid crisis and right ventricular dysfunction. Timing of surgery is the most crucial point of CHD management and relies on the case-by-case determination of the optimal compromise between tumour progression, cardiac symptoms and CS control.
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Cardiopatía Carcinoide , Neoplasias Intestinales , Tumores Neuroendocrinos , Humanos , Cardiopatía Carcinoide/diagnóstico , Cardiopatía Carcinoide/etiología , Cardiopatía Carcinoide/terapia , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , Neoplasias Intestinales/terapia , Neoplasias Intestinales/complicaciones , Morbilidad , SerotoninaRESUMEN
We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.
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COVID-19 , Diabetes Mellitus , Neoplasias Intestinales , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Persona de Mediana Edad , Anciano , COVID-19/epidemiología , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Estudios Prospectivos , Prueba de COVID-19 , SARS-CoV-2 , Tumores Neuroendocrinos/patología , Neoplasias Gástricas/patología , Neoplasias Intestinales/patologíaRESUMEN
BACKGROUND: There is no standard second-line treatment after platinum-etoposide chemotherapy for gastroenteropancreatic neuroendocrine carcinoma. We aimed to evaluate the efficacy of FOLFIRI plus bevacizumab, and FOLFIRI alone, in this setting. METHODS: We did a randomised, non-comparative, open-label, phase 2 trial (PRODIGE 41-BEVANEC) at 26 hospitals in France. We included patients aged 18 years or older with locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinoma or neuroendocrine carcinoma of unknown primary origin, documented progressive disease during or after first-line platinum-etoposide chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1; block size of three), without stratification, to receive FOLFIRI (irinotecan 180 mg/m2, calcium folinate 400 mg/m2 or levofolinate 200 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h) plus bevacizumab 5 mg/kg or FOLFIRI alone, intravenously, every 2 weeks until disease progression or unacceptable toxicity. Neither patients nor investigators were masked to group assignment. The primary outcome was overall survival at 6 months after randomisation, evaluated in the modified intention-to-treat population (all enrolled and randomly assigned patients who received at least one cycle of FOLFIRI). This study is now complete and is registered with ClinicalTrials.gov, NCT02820857. FINDINGS: Between Sept 5, 2017, and Feb 8, 2022, 150 patients were assessed for eligibility and 133 were enrolled and randomly assigned: 65 to the FOLFIRI plus bevacizumab group and 68 to the FOLFIRI group. 126 patients (59 in the FOLFIRI plus bevacizumab group and 67 in the FOLFIRI group) received at least one cycle of FOLFIRI and were included in the modified intention-to-treat population, 83 (66%) of whom were male and 43 (34%) were female, and the median age of the patients was 67 years (IQR 58-73). The primary tumour location was colorectal in 38 (30%) of 126 patients, pancreatic in 34 (27%), gastro-oesophageal in 22 (17%), and unknown in 23 (18%). After a median follow-up of 25·7 months (95% CI 22·0-38·2), 6-month overall survival was 53% (80% CI 43-61) in the FOLFIRI plus bevacizumab group and 60% (51-68) in the FOLFIRI group. Grade 3-4 adverse events that occurred in at least 5% of patients were neutropenia (eight [14%] patients), diarrhoea (six [10%]), and asthenia (five [8%]) in the FOLFIRI plus bevacizumab group, and neutropenia (seven [10%]) in the FOLFIRI group. One treatment-related death (ischaemic stroke) occurred in the FOLFIRI plus bevacizumab group. INTERPRETATION: The addition of bevacizumab did not seem to increase the benefit of FOLFIRI with regard to overall survival. FOLFIRI could be considered as a standard second-line treatment in patients with gastroenteropancreatic neuroendocrine carcinoma. FUNDING: French Ministry of Health and Roche SAS.
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Isquemia Encefálica , Carcinoma Neuroendocrino , Neutropenia , Accidente Cerebrovascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Bevacizumab , Platino (Metal) , Etopósido , Isquemia Encefálica/inducido químicamente , Isquemia Encefálica/tratamiento farmacológico , Accidente Cerebrovascular/inducido químicamente , Accidente Cerebrovascular/tratamiento farmacológico , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Following European guidelines, patients with aggressive metastatic or locally advanced, non-resectable, duodeno-pancreatic (DP) neuroendocrine tumours (NETs) should receive systemic combination chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases with or without significant hepatic invasion (>30-50%), and/or bone metastases. METHODS: This academic randomised, double-blind, placebo-controlled phase II study aims to evaluate lanreotide autogel 120 mg (LAN) as maintenance treatment after at least 2 months of first-line treatment (L1) in aggressive G1-G2 DP-NET. Patients were randomly assigned in a 1:1 ratio to receive LAN or placebo (PBO), every 28 days, until progression or toxicity. The primary end-point was progression-free survival (PFS) at 6 months. RESULTS: Among the 118 planned patients, 53 were included. Of these, 81.1% had a G2 tumour, and 90.6% had metastatic disease. L1 therapy consisted of chemotherapy (96.8%). Median duration of L1 was 4.6 months (range: 2.0-7.7). At the time of randomisation, 81.1% of patients had stable disease. Median follow-up was 27.0 months (95% CI: 19.5; 31.2). PFS at 6 months was 73.1% (90% CI: 55.3; 86.6) in LAN versus 54.2% (90% CI: 35.8; 71.8) in PBO. Median PFS was 19.4 months (95% CI: 7.6; 32.6) and 7.6 months (95% CI: 3.0; 9.0), respectively. Median overall survival was 41.9 months in PBO and was not reached in LAN. The toxicity profile was mainly grade 1-2 expected toxicities. CONCLUSIONS: The encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed. TRIAL REGISTRATION: NCT02288377 (clinicaltrials.gov).
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Tumores Neuroendocrinos , Neoplasias Pancreáticas , Péptidos Cíclicos , Somatostatina , Humanos , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Péptidos Cíclicos/uso terapéutico , Somatostatina/análogos & derivados , Somatostatina/uso terapéuticoRESUMEN
Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of RB transcriptional corepressor 1 (RB1) status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicentre study. NEC patients treated with 2L and further, with tissue samples available, were included. RB1 status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61 years) included, there were 73 small-cell NEC (60%), 34 large-cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastroenteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an 'adenocarcinoma-like' or a 'neuroendocrine-like' 2L or according to the RB1 status. Thoracic NEC primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months, respectively. In the 94 patients with a relapse-free interval of ≥3 months after first-line platinum-etoposide chemotherapy, the median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (P = 0.043). EBR could be the best 2L option for patient with initial response to first-line platinum-etoposide lasting at least 3 months. RB1 status does not provide prognostic information in this setting.
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Carcinoma Neuroendocrino , Etopósido , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/patología , Etopósido/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Pronóstico , Estudios RetrospectivosRESUMEN
Purpose: To improve neuroendocrine neoplasm (NEN) management, the European Neuroendocrine Tumor Society (ENETS) recognised 62 Centers of Excellence (CoE). This retrospective study compares conformity of patients' initial management within vs outside an ENETS CoE with clinical practice guidelines (CPGs). Methods: Patients diagnosed with a NEN between August 2018 and July 2020 and presented in the Lyon-CoE Multidisciplinary Tumour Board (MDT) were included. Factors potentially associated with the conformity of initial management (work-up and first treatment) to CPG underwent univariate and multivariate analyses. Results: Among the 615 included patients, 170 (27.6%) were initially managed in the CoE and 445 (72.4%) were only presented at the CoE-MDT. Patients in the CoE group more often had intestinal or pancreatic primaries, metastatic disease (61.8% vs 33%), hereditary syndrome, and a functioning tumour. Work-up conformity was 37.1% in the CoE (vs 29.9%, P = 0.09); this was 95.8% for the first treatment (vs 88.7%, P = 0.01). After multivariate analysis, CPG conformity was significantly higher for patients managed in the CoE, for younger patients, for those having a grade 1-2 tumour, and a genetic syndrome. Pancreatic and small intestinal (SI) NET surgeries performed in the CoE had a higher splenic preservation rate during left pancreatectomy, better detection of multiple tumours in SI surgeries, and higher number of resected lymph nodes. Conclusions: Given the widespread observance of CPG, not all patients require management in the CoE. Referral should be considered for more complex cases such as metastatic diseases, G2 tumours, or carcinoid syndromes. Finally, we should encourage the centralization of NET surgery.
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INTRODUCTION: Approval of sunitinib and everolimus for the treatment of progressive, unresectable or metastatic well-differentiated pancreatic neuroendocrine tumors (pNETs) was obtained in France in 2011 and 2012, respectively. OPALINE was set up as an observational study to evaluate the efficacy of sunitinib and everolimus compared to usual pNET treatments of chemotherapies and somatostatin analogues that had been previously recommended by the health authorities. METHODS: The OPALINE study assessed the efficacy of everolimus and sunitinib in terms of survival, disease progression and tolerance. Patients (N = 144) were enrolled from May 2015 to September 2017, and their disease characteristics were analyzed from diagnosis to 2 years post-enrollment. RESULTS: At inclusion most patients had comorbidities, and about 95% presented metastases. Patients received on average 3.2 lines of treatment from diagnosis to inclusion and two lines throughout the 2-year follow-up. Seventy-nine patients (59.0%) received at least one targeted therapy (TT) during their care path. For these patients, the overall survival (OS) was approximatively 176.5 months (95% CI: 97.2-not evaluable), with a 2-year survival rate estimated at 93.6% (SD 2.6%). Similar survival rates were observed whether the TTs were prescribed sooner or later in the treatment path. The main reasons for discontinuation of TTs were disease progression (54 patients) and adverse events (26 patients). Most patients receiving TTs did not change their dose during the follow-up reflecting the good treatment tolerability over time. No new safety alert was reported for everolimus and sunitinib during this study. CONCLUSION: Given their good tolerance and positive impact on estimated OS, the two TTs have an important role to play in the care path of patients with pNETs. GOV NATIONAL CLINICAL TRIAL NUMBER: NCT02264665.
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Antineoplásicos , Neoplasias Primarias Secundarias , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Everolimus/uso terapéutico , Humanos , Tumores Neuroectodérmicos Primitivos/inducido químicamente , Tumores Neuroectodérmicos Primitivos/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Sunitinib/uso terapéuticoRESUMEN
INTRODUCTION: MTDM dedicated to geriatric oncology are held at the E. Herriot hospital in Lyon. They bring together oncologist and geriatrician to optimize, through their complementary expertise, the care plan for elderly cancer patients. The aim is to demonstrate the value of these MTDMs and to describe the follow-up of oncological and geriatric recommendations. METHODS: This is a descriptive, prospective, non-interventional study analyzing the MTDMs dedicated to patients over 70years old with cancer. All patients underwent a comprehensive geriatric assessment (CGA) with a four-month follow-up. RESULTS: One hundred twenty-one patients were included with a G8 score≤14 (93 %), a slightly diminishing independence ADL<6 (36%) and IADL<4 (42%). The median CIRS-G is eight with on average, three geriatric syndromes/patient. Most cancers are non-metastatic. When oncological treatment is recommended (80 %), it is mostly curative (58 %). Geriatric recommendations were made for 75 % of patients. At four months, four patients were lost to follow-up and 34 died. No significant change in the dependency level was found. In 75 % of cases, at least one geriatric recommendation were followed and 77 % of oncological recommendations. CONCLUSION: The recommendations could be followed at four months; they were carried out in a comparable way whether they were oncological or geriatric. These MTDMs specializing in geriatric oncology appear to be beneficial in the geriatric oncology decision-making process. It is important to continue and strengthen this co-management.
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Evaluación Geriátrica , Neoplasias , Anciano , Estudios de Seguimiento , Humanos , Neoplasias/terapia , Grupo de Atención al Paciente , Estudios ProspectivosRESUMEN
The annual prevalence of metastatic neuroendocrine tumours (mNETs) is rising, leading to significant healthcare costs. The present study aimed to describe healthcare resource use (HRU) and the corresponding costs among patients with mNETs, according to primary tumour location, functioning status and type of treatments. The LyREMeNET study included consecutive mNET patients with a diagnosis performed between January 2010 and December 2017, who were seen at least once in the ENETS center of excellence in Lyon. The median HRU and costs per patient were estimated, up to 3 years before and after the diagnosis. The Cancer database of the center was linked to the French national health data system. HRU and related costs were described per person per month (PPPM). Among 316 patients presenting with a mNET, 48.4% had a small-intestinal mNET, 32.3% had a pancreatic mNET and 39.2% had carcinoid syndrome. The mean overall cost increased from 615 to 2875 PPPM between the years preceding and following the diagnosis, and remained above 2500 in the two subsequent years. The two main cost drivers of total healthcare expenditure were drugs (1161) and hospital stay (662). Median costs of mNETs arising from pancreas and small intestine were 2325 and 2540 PPPM, respectively. Costs were higher in patients with a functional mNET (2807 PPPM for carcinoid syndrome) and during peptide receptor radionuclide therapy (PRRT) (8835 PPPM). The highest overall cost was found during the first year following the diagnosis. Cost of care was higher for small intestine mNETs, for functional mNETs and during peptide receptor radionuclide therapy.
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Tumor Carcinoide , Tumores Neuroendocrinos , Costos de la Atención en Salud , Humanos , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/terapia , Radioisótopos , Receptores de PéptidosRESUMEN
INTRODUCTION: This prospective, single-arm, phase 2 study assessed the efficacy and safety of lanreotide autogel (LAN) administered at a reduced dosing interval in patients with progressive neuroendocrine tumours (NETs) after LAN standard regimen. METHODS: Patients had metastatic or locally advanced, grade 1 or 2 midgut NETs or pancreatic NETs (panNETs) and centrally assessed disease progression on LAN 120 mg every 28 days. They were treated with LAN 120 mg every 14 days for up to 96 weeks (midgut cohort) or 48 weeks (panNET cohort). The primary end-point was centrally assessed progression-free survival (PFS). PFS by Ki-67 categories was analysed post hoc. Secondary end-points included quality of life (QoL) and safety. RESULTS: Ninety-nine patients were enrolled (midgut, N = 51; panNET, N = 48). Median (95% CI) PFS was 8.3 (5.6-11.1) and 5.6 (5.5-8.3) months, respectively. In patients with Ki-67 ≤ 10%, median (95% CI) PFS was 8.6 (5.6-13.8) and 8.0 (5.6-8.3) months in the midgut and panNET cohorts, respectively. Patients' QoL did not deteriorate during the study. There were no treatment-related serious adverse events and only two withdrawals for treatment-related adverse events (both in the panNET cohort). CONCLUSIONS: In patients with progressive NETs following standard-regimen LAN, reducing the dosing interval to every 14 days provided encouraging PFS, particularly in patients with a Ki-67 ≤ 10% (post hoc); no safety concerns and no deterioration in QoL were observed. Increasing LAN dosing frequency could therefore be considered before escalation to less well-tolerated therapies.
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Antineoplásicos/administración & dosificación , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Péptidos Cíclicos/administración & dosificación , Somatostatina/análogos & derivados , Anciano , Antineoplásicos/efectos adversos , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Geles , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Péptidos Cíclicos/efectos adversos , Supervivencia sin Progresión , Estudios Prospectivos , Calidad de Vida , Somatostatina/administración & dosificación , Somatostatina/efectos adversosRESUMEN
A rechallenge is common after the initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with a lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET, and to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause of > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (cohort A). The primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (cohort B). We found that Cohort A included 62 patients (median Ki67 8%), for whom ALK1 followed by a pause achieved an objective response rate of 55% and a PFS1 of 23.7 months (95% IC, 19.8-27.6). ALK2 achieved no objective response and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1-11.3). At multivariable analysis, a hormonal syndrome (P = 0.032) and a pause longer than 12 months (P = 0.041) were associated with a longer PFS2. In cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18-105) before ALK to 100 (IQR 56-180) after ALK (P = 0.003). We conclude that after the initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain the low efficacy of ALK rechallenge.
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Alquilantes , Antineoplásicos Alquilantes , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Humanos , Metástasis de la Neoplasia , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Calidad de Vida , Estudios Retrospectivos , Resultado del Tratamiento , Proteínas Supresoras de Tumor/metabolismoRESUMEN
OBJECTIVE: Literature on patient-reported outcomes (PRO) of carcinoid syndrome symptoms (CSS) is scarce. We used a patient-reported outcome measure (PROM) to evaluate CSS, the domains of daily life impacted by CSS, the main symptoms that affect daily life, its change according to clinical, biological and morphological evolution, and the risk factors for a poor PRO-CSS score. METHODS: Patients completed the PRO-CSS, EORTC-QLQ30, and GI-NET21 questionnaires at the time of their clinical, laboratory, and morphological assessments in a multicentre French cohort study from February 2019 to May 2020. RESULTS: In total, 147 patients with metastatic ileal (n =126), lung (n =20), or unknown primitive neuroendocrine tumour but high 5-hydroxyindole-3-acetic acid level (n =1) were included; 42 (32%) received an above-label dose of somatostatin analogues. Fifty-one (35%) patients had a poor PRO-CSS score. Travelling and food restriction were the two main domains affected. Diarrhoea (mean: 2.3/5 on Likert scale), imperiousness (mean of 2.5/5), fatigue (2.2/5), abdominal pain (1.7/5), and flushing episodes (1.5/5) were the main symptoms affecting daily life. The PRO-CSS score was not correlated to the clinical assessment performed by physicians at the baseline and during the follow-up. Patients with a poor PRO-CSS score had a higher tumour burden. CONCLUSIONS: PROM-CSS may help physicians make an objective assessment of CSS and its impact in daily practice; this tool could become a key evaluation criterion in clinical trials focusing on CSS.
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Síndrome Carcinoide Maligno/terapia , Anciano , Estudios de Cohortes , Femenino , Alimentos , Francia , Humanos , Ácido Hidroxiindolacético/sangre , Masculino , Síndrome Carcinoide Maligno/complicaciones , Síndrome Carcinoide Maligno/psicología , Persona de Mediana Edad , Metástasis de la Neoplasia , Tumores Neuroendocrinos , Medición de Resultados Informados por el Paciente , Estudios Prospectivos , Calidad de Vida , Autoinforme , Encuestas y Cuestionarios , Viaje , Resultado del Tratamiento , Carga TumoralRESUMEN
INTRODUCTION: Streptozocin can impair renal function. The purpose of this study was to evaluate the evolution of renal function in patients receiving this anti-mitotic for the treatment of locally advanced/metastatic digestive well differentiated neuroendocrine tumours. METHODS: A prospective and a retrospective cohort of patients with normal baseline renal function were analysed. The primary endpoint was the incidence of a decrease in the estimated glomerular filtration rate ≥ 25% during treatment. Secondary endpoints were the evaluation of glomerular filtration rate changes, the impact of combined nephrotoxic treatments, other toxicities, compliance, and the objective response rate. RESULTS: After screening 142 patients, 27 were included in the prospective and 84 in the retrospective cohort. A decrease in estimated glomerular filtration rate ≥ 25% was observed in 32 patients (30%): respectively four (15.4%) and 28 patients (34.1%) among respectively 26 and 82 patients with numerous measures (Pâ¯=â¯0.0097). Altogether, 39 patients (35%) experienced grade 1-2 renal toxicity, while no grade 3-4 occurred in the prospective and 1 occurred in the retrospective cohort. Renal toxicity was more frequent in the retrospective cohort with a less careful follow up. As best responses, objective response was achieved in 27% of patients with pancreatic primary tumours, disease control in 78.9% of patients with pancreatic primary tumours, in 87% of those with small bowel tumours and in 72.7% of patients with other primary locations. CONCLUSIONS: Strongly recommended for pancreatic NET, streptozocin is associated with frequent mild renal toxicity but low occurrence of renal impairment in patients with baseline normal renal function and under adequate hydration.
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Neoplasias del Sistema Digestivo , Riñón , Tumores Neuroendocrinos , Estreptozocina , Neoplasias del Sistema Digestivo/tratamiento farmacológico , Humanos , Riñón/fisiología , Tumores Neuroendocrinos/tratamiento farmacológico , Estudios Prospectivos , Estudios Retrospectivos , Estreptozocina/uso terapéutico , Resultado del TratamientoRESUMEN
In a previous phase II study (THERAPY), cetuximab and trastuzumab combination, as second-line after progression with gemcitabine, showed disease stabilization in 27% of 33 patients with pancreatic carcinoma. In the present phase II multicenter study, we assessed the efficacy and tolerance of gemcitabine, trastuzumab plus erlotinib as first-line treatment of metastatic pancreatic cancer. The primary endpoint was disease control rate (DCR, RECIST v.1); secondary endpoints were progression-free (PFS), overall (OS) survival and toxicity (NCI-CTCAE v3.0). Ancillary study addressed the predictive value of both EGFR/HER2 expression and KRAS mutational status. Sixty-three patients from four centers were included (62 evaluable for toxicity, 59 for efficacy), median age was 62 years (35-77), 59.7% men. The median treatment duration was 16.1 weeks (2.1-61). Eleven patients (19%) reported a partial tumor response, and 33 (56%) disease stabilization. DCR was 74.6% (95%CI: 61.8-85.0; 44/59 patients). After a median follow-up of 23.3 months (0.6-23.6), median PFS was 3.5 months (95%CI: 2.4-3.8) and median OS 7.9 months (95%CI: 5.1-10.2). PFS was significantly longer in patients with grade ≥ 2 cutaneous toxicities vs patients with grade 0-1 toxicities (HR = 0.55, 95%CI: 0.33-0.92, P = .020). Expression of EGFR and HER2 was correlated with PFS and OS in multivariate analysis; HER2 expression was correlated with the tumor response. Main severe toxicities were neutropenia (32%), cutaneous rash (37%) and thrombosis/embolisms (35.5%). This triplet combination is effective in terms of disease control, PFS and OS, and acceptable for safety. A larger study to investigate this combination compared to the standard regimen should be discussed.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Desoxicitidina/análogos & derivados , Clorhidrato de Erlotinib/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Trastuzumab/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Receptores ErbB/genética , Clorhidrato de Erlotinib/efectos adversos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Pancreáticas/genética , Receptor ErbB-2/genética , Análisis de Supervivencia , Trastuzumab/efectos adversos , Resultado del Tratamiento , GemcitabinaRESUMEN
INTRODUCTION: Gastroenteropancreatic neuroendocrine carcinomas (GEPNEC) are characterized by a heterogeneous molecular profile and a poor prognosis. Circulating tumour DNA (ctDNA) analysis may be useful for NEC management. This study aimed at describing ctDNA mutations, to assess their predictive value for response to chemotherapies, and their change according to disease progression. METHODS: The CIRCAN-NEC study included patients with GEPNEC or NEC from an unknown primary, scheduled to begin first- or second-line chemotherapy. Blood samples were collected prior to chemotherapy initiation, at first evaluation, and during disease progression. ctDNA was sequenced by next-generation sequencing (NGS). Molecular response was defined as a decrease of at least 30% of the mutant allele fraction. RESULTS: All 24 patients included received platinum-etoposide first-line chemotherapy; 19 received a FOLFIRI-based post-first-line regimen. Twenty-two patients had at least one driver mutation: TP53 (n = 21), RB1 (n = 2), KRAS (n = 4), and BRAF (n = 3). Ten (42%) had an "adenocarcinoma-like" profile. Five of 6 patients with matching ctDNA/tissue NGS harboured at least one concordant mutation (44% concordance at the gene level). The concordance rate between ctDNA mutation/immunohistochemistry profile was 64% (7/11) for TP53/p53+ and 14% (1/7) for RB1/pRb-. In this pilot study including few patients by subgroups, patients with KRAS (HR = 3.60, 95% CI [1.06-12.04]) and BRAF (HR = 4.25, 95% CI [1.11-16.40]) mutations had shorter progression-free survival (PFS) under platinum-etoposide, while the 2 patients with RB1 mutations had shorter PFS under FOLFIRI-based chemotherapy. Twenty-eight periods of treatment were assessed: 10 patients had a molecular response (7/10 had a morphological response), which was associated with longer PFS (HR = 0.37, 95% CI [0.15; 0.91]). CONCLUSION: This pilot study shows a high sensitivity of ctDNA assessment, which is encouraging for the future management of GEPNEC (tumour molecular diagnosis and evaluation of disease progression).
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Antineoplásicos/farmacología , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/secundario , ADN Tumoral Circulante/genética , Neoplasias Intestinales/patología , Neoplasias Primarias Desconocidas/patología , Tumores Neuroendocrinos/patología , Evaluación de Resultado en la Atención de Salud , Neoplasias Pancreáticas/patología , Neoplasias Gástricas/patología , Adulto , Anciano , Antineoplásicos/administración & dosificación , Carcinoma Neuroendocrino/tratamiento farmacológico , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
INTRODUCTION: The characteristics, prognostic factors, and management of duodenal neuroendocrine neoplasms (dNEN) are ill-defined, given their rarity. Whether nonsurgical management might be appropriate for patients with nonmetastatic dNEN and a good prognosis, as is the case for pancreatic NEN (pNEN), is unknown. We aimed to describe the management and prognosis of nonmetastatic dNEN patients. METHODS: All consecutive patients with nonmetastatic dNEN managed between 1981 and 2018 in 2 expert centers were included. Recurrence-free survival (RFS) and factors associated with recurrence were estimated. RESULTS: A total of 145 patients with dNEN were included. Twenty-eight patients with sporadic, nonfunctioning, small (median 7 mm) dNEN underwent endoscopic resection, with a 5-year RFS rate of 89.4%. Local recurrence occurred in 2 patients, who underwent surgery with no new events. The 5-year RFS rate was 87.9% in patients who underwent surgery. Upon univariate analysis, age, size, Ki67 index, and lymph node involvement (LN+) were significantly associated with worse RFS for all dNEN treated (endoscopy/surgery); multivariate analysis found that age, size, and LN+ were associated with worse RFS. CONCLUSION: Selected nonmetastatic dNEN had a favorable outcome, and a less invasive therapeutic strategy appeared more suitable than oncological surgery.
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Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/terapia , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , Evaluación de Procesos y Resultados en Atención de Salud , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Neoplasias Duodenales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/cirugía , Estudios RetrospectivosRESUMEN
We present the case of a 70-year-old man with intramyocardial solitary metastasis from a carcinoid bowel tumor. One year previously, he had undergone distal ileum resection for a neuroendocrine tumor. Asymptomatic recurrence was diagnosed with the combination of elevated chromogranin A serum level and somatostatin receptor scintigraphy. The tumor was located on the right ventricle free wall, without obstruction of the right ventricular outflow tract and absence of carcinoid syndrome or liver involvement. Complete resection was obtained under cardiopulmonary bypass. The patient is currently alive without disease 2 years after surgery. Oncologists should be aware of the heart as a possible site of neuroendocrine metastatic disease. This case highlights the value of positron emission tomography with somatostatin analogs for earlier and more frequent metastasis detection. Persistent remission can be obtained with complete surgical resection when the metastatic tumor is localized in the right ventricle without evidence of carcinoid heart disease.
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Tumor Carcinoide , Tumores Neuroendocrinos , Anciano , Humanos , Masculino , Recurrencia Local de Neoplasia , Tumores Neuroendocrinos/cirugía , Tomografía de Emisión de PositronesRESUMEN
INTRODUCTION: Small-intestinal neuroendocrine tumors (SI-NET) are situated preferentially within the ileum. The aim was to describe a potential difference in location between unifocal and multiple ileal-NET. PATIENTS AND METHODS: Between December 2010 and December 2019, all consecutive patients who underwent resection in our European Neuroendocrine Tumor Society Center of Excellence, of at least 1 non-duodenal SI-NET, were retrospectively included. The main objective was to prove that multiple ileal-NET were mostly located on the left side of the superior mesenteric artery (SMA) axis (defined as 40 cm from the ileocecal valve), and unifocal ones on the right side. RESULTS: Ninety-four patients were included, 6 with unifocal jejunal-NET located 35 cm (range, 10-60) from the duodenojejunal angle (DJA), 44 (47%) with unifocal ileal-NET and 44 (47%) with multiple ileal-NET. The median number of tumors in multiple ileal-NET was 7 (range, 2-95), within a median small bowel segment of 105 cm (10-240). The median length between the proximal tumor and the DJA was 428 cm (300-635) and 540 cm (350-725) for the distal one; 40 (91%) of them were located on the left side of the SMA axis. In contrast, unifocal ileal-NET were located at a median distance of 577 cm (305-820) from the DJA (p < 0.001, compared to multiple ileal-NET); 30 (68%) of them were on the right side of the SMA axis (p < 0.001). CONCLUSION: Multiple ileal-NET are mostly located on the left side of the SMA axis. Further studies are warranted to explore the embryological origin of unifocal versus multiple ileal-NET.