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1.
Lancet ; 403(10431): 1061-1070, 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38402886

RESUMO

BACKGROUND: No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. METHODS: FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. FINDINGS: From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock. INTERPRETATION: This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. FUNDING: French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.


Assuntos
Neoplasias das Glândulas Suprarrenais , Hipertensão , Feocromocitoma , Adulto , Humanos , Adolescente , Sunitinibe/uso terapêutico , Feocromocitoma/tratamento farmacológico , Feocromocitoma/etiologia , Intervalo Livre de Progressão , Hipertensão/etiologia , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/etiologia , Método Duplo-Cego , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
2.
Br J Haematol ; 204(3): 1054-1060, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38195958

RESUMO

We report a large series of 40 patients presenting EPAS1-mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1-PGLs, which should be taken into account in their management and surveillance.


Assuntos
Neoplasias das Glândulas Suprarrenais , Hemoglobinopatias , Paraganglioma , Humanos , Hemoglobinas/genética , Hipóxia/genética , Mutação , Paraganglioma/genética , Paraganglioma/patologia
3.
Cancer ; 128(17): 3185-3195, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35737639

RESUMO

BACKGROUND: CC-90011 is an oral, potent, selective, reversible inhibitor of lysine-specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long-term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first-in-human study of CC-90011. METHODS: CC-90011-ST-001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015-005243-13) is a phase 1, multicenter study in which patients received CC-90011 once per week in 28-day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). RESULTS: Sixty-nine patients were enrolled, including 50 in the dose-escalation arm and 19 in the dose-expansion arm. Thrombocytopenia was the most common treatment-related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose-escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose-expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC-90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin-releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte-to-macrophage differentiation-associated. CONCLUSIONS: The safety profile of CC-90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once-per-week dosing support further exploration of CC-90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies.


Assuntos
Linfoma de Zona Marginal Tipo Células B , Neoplasias , Histona Desmetilases , Humanos , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Compostos Orgânicos
4.
Eur J Nucl Med Mol Imaging ; 49(7): 2401-2413, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35149914

RESUMO

PURPOSE: Bone metastases (BM) from differentiated thyroid carcinoma (DTC) impact negatively the quality of life and the life expectancy of patients. The aim of the study was (a) to evaluate the overall survival (OS) and prognostic factors of OS and (b) to assess predictive factors of complete BM response (C-BM-R) using radioiodine treatment (RAI) either alone or in association with focal treatment modalities. METHODS: A total of 178 consecutive DTC patients harbouring BM, treated between 1989 and 2015, were enrolled in this retrospective study conducted in two tertiary referral centers. OS analysis was performed for the whole cohort, and only the 145 considered non-RAI refractory patients at BM diagnosis were evaluated for C-BM-R following RAI. RESULTS: The median OS from BM diagnosis was 57 months (IQR: 24-93). In multivariate analysis, OS was significantly reduced in the case of T4 stage, 18FDG uptake by the BM and RAI refractory status. Among the 145 DTC considered non-RAI refractory patients at BM diagnosis, 46 patients (31.7%) achieved a C-BM-R following RAI treatment, either alone in 32 (18%) patients or in association with focal BM treatment modalities in 14. The absence of extra-skeletal distant metastasis and of 18FDG uptake in BM were predictive for C-BM-R. CONCLUSIONS: In nearly one-third of DTC patients with RAI avid BM, RAI alone or in combination with BM focal treatment can induce C-BM-R. The presence of 18FDG uptake in BM is associated with an absence of C-BM-R and with a poor OS. 18FDG PET-CT should be performed when BM is suspected.


Assuntos
Adenocarcinoma , Neoplasias Ósseas , Neoplasias da Glândula Tireoide , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Fluordesoxiglucose F18 , Humanos , Radioisótopos do Iodo/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Qualidade de Vida , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/patologia
5.
Neuroendocrinology ; 112(6): 537-546, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34348346

RESUMO

INTRODUCTION: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs); however, the available data are limited. Our aim was to assess the efficacy of FOLFOX (association of 5-fluorouracil with oxaliplatin) in a large series of patients with advanced digestive NETs. METHODS: All patients with advanced digestive well-differentiated NETs treated with at least 3 cycles of FOLFOX between January 2004 and December 2018 in 12 centers from the French Group of Endocrine Tumors were included. Tumor response rate according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, progression free survival (PFS), and overall survival, as well as prognostic factors, were analyzed retrospectively. RESULTS: One hundred fifty-five patients were included. Primary tumor locations were pancreas (n = 89), small intestine (n = 40), unknown with no evidence for lung primary (n = 13), stomach (n = 7), and rectum (n = 6). Median Ki-67 was 10%, and 65% of the tumors were grade 2. The partial response rate was 30% for pancreatic NETs, 12.5% for small intestine NETs, 38.5% for unknown primary NETs, 14% for gastric NETs, and 17% for rectal NETs. Significant prognostic factors for poor PFS after FOLFOX were progressive disease at the beginning of treatment (hazard ratio [HR] = 1.83, p = 0.007), hepatic involvement superior to 50% (HR = 2.67, p = 0.0001), and rectal primary tumor location (HR = 2.6, p = 0.0036). Among pancreatic NETs, insulinomas had a better median PFS (22 months) than other pancreatic NETs (9 months, p = 0.026) and showed a high rate (8/9) of serum glucose normalization. CONCLUSIONS: FOLFOX shows a promising antitumor activity in advanced digestive NETs. Rapid symptomatic response is observed in metastatic insulinomas.


Assuntos
Insulinoma , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/uso terapêutico , Humanos , Tumores Neuroendócrinos/patologia , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Resultado do Tratamento
6.
Support Care Cancer ; 31(1): 41, 2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36525139

RESUMO

PURPOSE: Kinase inhibitors (KI) and antibodies targeting the VEGF pathway are approved in a broad spectrum of cancers and associated with an increased risk of bleeding and thromboembolic events (TE). The use of direct oral anticoagulants (DOACs) apixaban and rivaroxaban is increasing in cancer patients, but limited data are available for patients receiving anti-VEGF agents. METHODS: To assess safety of DOAC with concomitant anti-VEGF agents, a retrospective chart review of all patients receiving concomitantly DOAC and anti-VEGF agents was performed from 2013 to 2020 in our center. Data on demographics, safety, and time on treatment were collected. Main outcome was safety (bleeding and thromboembolic events). RESULTS: Of 92 patients (median age 66 years (IQR: 59-72)), 40 were treated with KI and 52 with bevacizumab. The most frequent primary tumor sites were colon/rectum (24%), kidney (21%), ovary (13%), lung (11%), soft tissue sarcoma (10%), and thyroid (9%); 2% had brain metastases. Apixaban 5 mg bid (n = 41) or rivaroxaban 20 mg daily (n = 51) were given for TE (65%), atrial fibrillation (32%), or other indications (3%). The median duration of concomitant treatment was 4.8 months (95%CI: 0.7-50.0) with bevacizumab and 11.7 months (95%CI: 0.1-53.8) with KI. Grade ≥ 3 bleeding events occurred in 5 patients (5%): 4 patients receiving bevacizumab (one grade 5 upper digestive tract bleeding and three grade 3 rectal or vaginal hemorrhages) and 1 patient under cabozantinib for kidney cancer with endobronchial metastasis (grade 3 hemoptysis). Grade ≥ 3 TE occurred in 8 patients (9%): 7 patients receiving bevacizumab (including one grade 5 pulmonary embolism), and one patient receiving sunitinib (grade 3 pulmonary embolism). Median time-to-event (bleeding or thrombotic event) was not reached (NR) (95%CI: 76.9-NR) for KI and 86.9 months (95%CI: 42.9-148.0) for bevacizumab. CONCLUSIONS AND RELEVANCE: In our experience, the use of DOAC was safe in selected patients treated with KI, but unclear with bevacizumab. More data are needed to endorse guidelines in this specific group of patients.


Assuntos
Neoplasias , Embolia Pulmonar , Feminino , Humanos , Idoso , Rivaroxabana/efeitos adversos , Estudos Retrospectivos , Dabigatrana/efeitos adversos , Anticoagulantes/efeitos adversos , Bevacizumab/efeitos adversos , Administração Oral , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Neoplasias/tratamento farmacológico
7.
Ocean Coast Manag ; 228: None, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36133796

RESUMO

Underwater noise from human activities is now widely recognised as a threat to marine life. Nevertheless, legislation which directly addresses this source of pollution is lacking. The first (and currently only) example globally is Descriptor 11 of the Marine Strategy Framework Directive (MSFD), adopted by the European Union in 2008, which requires that levels of underwater noise pollution do not adversely affect marine ecosystems. The MSFD has stimulated a concerted research effort across Europe to develop noise monitoring programmes and to conduct research towards specifying threshold values which would define 'Good Environmental Status' (GES) for underwater noise. Here, we chart the progress made during the first decade of Descriptor 11's implementation: 2010-2020. Several international joint monitoring programmes have been established for impulsive and continuous noise, enabling ecosystem-scale assessment for the first time. Research into the impact of noise on individual animals has grown exponentially, demonstrating a range of adverse effects at various trophic levels. However, threshold values for GES must be defined for 'populations of marine animals.' Population-level consequences of noise exposure can be modelled, but data to parameterise such models are currently unavailable for most species, suggesting that alternative approaches to defining GES thresholds will be necessary. To date, the application of measures to reduce noise levels (quieting/noise abatement) has been limited. To address this, the EU in 2021 identified an explicit need to reduce underwater noise pollution in its waters. Delivering on this ambition will require further research focused on the development and implementation of quieting measures.

8.
Neuroendocrinology ; 111(1-2): 139-145, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-31639792

RESUMO

BACKGROUND: Cancer survivors have a 14% increased risk of developing a malignancy compared with the general population. Second radiation-induced malignancies with different histologies have been described in different organs. Based on individual observations, we hypothesized that neuroendocrine carcinoma (NEC) could arise in irradiated organs. METHODS: In a retrospective analysis of Gustave Roussy database of NEC patients (small cell lung cancer excluded) diagnosed as a second cancer, we looked for the frequency of grade 3 NEC that arose in patients who had received previous radiation therapy for a first cancer. Radiation therapy for the first cancer, dose, location of radiation therapy, pathological characteristics, overall survival, and response to treatment of secondary NEC were analyzed. RESULTS: From January 1995 to December 2017, 847 cases of NEC were seen at Gustave Roussy. Among them, 95 (11.2%) patients had a history of previous malignancy of which 36 (4%) had been treated with radiation therapy. Out of these 36 patients, 12 (1.4% of all NEC patients) developed a NEC within the previous irradiated organ (median dose of 50 Gy, range 36-67.5). Most frequent first cancers were breast cancer (n = 4) and Hodgkin lymphoma (n = 3). NEC arose within a median time of 21.7 years (range 5.1-36.4) from radiation in the thorax (n = 5), digestive tract (n = 3), and other sites. Five large cell NEC, 3 small cell NEC, 1 mixed neuroendocrine neoplasm and 3 not otherwise specified NEC were diagnosed. Ten patients had stage IV disease at diagnosis; median overall survival was 37.8 months (95% CI [17.6 to NA]). Three patients (25%) achieved complete response with multimodal treatment. CONCLUSIONS: NEC can arise from previously irradiated organs and may have a better outcome in this setting. Other risk factors should be investigated to explain the high rate of previous cancer in this population of neuroendocrine neoplasm.


Assuntos
Carcinoma Neuroendócrino/etiologia , Neoplasias Induzidas por Radiação , Segunda Neoplasia Primária/etiologia , Adolescente , Adulto , Idoso , Carcinoma Neuroendócrino/terapia , Criança , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/radioterapia , Neoplasias Induzidas por Radiação/terapia , Segunda Neoplasia Primária/terapia , Radioterapia/efeitos adversos , Estudos Retrospectivos , Centros de Atenção Terciária
9.
Neuroendocrinology ; 111(6): 599-608, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32512564

RESUMO

INTRODUCTION: Peritoneal metastases from neuroendocrine tumors are associated with a bad prognosis. The objective of our study was to evaluate whether surgical resection could lead to prolonged survival in selected patients. This survival was compared to that of patients operated for liver metastasis. METHODS: From our prospectively maintained database we included 88 patients who underwent the complete resection of peritoneal and/or liver metastasis between January 1995 and December 2016 in Gustave-Roussy. Three resection groups were compared: peritoneal metastasis alone, liver metastasis alone, and the combined resection of liver and peritoneal metastases. RESULTS: The median peritoneal cancer index was 10 in the peritoneal group and 11 in the peritoneal + liver group. The 5-year overall survival was 81% (60-100) in the peritoneal group compared to 78% (65.2-92.8) in the liver group, and 72% (58.7-89.7) in the peritoneal + liver group (p = 0.71). The 3-year disease-free survival reached 26.9% (16.1-45.1) in the liver group, 12.5% (2.3-68.2) in the peritoneal group, and 32.4% (19.9-52.6) in the combined liver + peritoneal group (p = 0.45). In the univariate analysis, the prognosis factors for a longer survival were: small bowel primary tumor origin, low preoperative chromogranin A level, and tumor grade ≤1. CONCLUSION: Despite a high recurrence rate, long-term overall survival can be achieved after the resection of peritoneal metastasis in selected patients. This survival is comparable to that of patients operated for liver metastasis only. Surgery should stand as a standard treatment for peritoneal metastases in patients with resectable disease.


Assuntos
Neoplasias Hepáticas/cirurgia , Tumores Neuroendócrinos/patologia , Avaliação de Resultados em Cuidados de Saúde , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/cirurgia , Intervalo Livre de Doença , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Peritoneais/secundário
10.
Ann Surg ; 272(6): 1094-1101, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-30585820

RESUMO

OBJECTIVE: To assess the distant metastatic potential of duodeno-pancreatic neuroendocrine tumors (DP-NETs) in patients with MEN1, according to functional status and size. SUMMARY BACKGROUND DATA: DP-NETs, with their numerous lesions and endocrine secretion-related symptoms, continue to be a medical challenge; unfortunately they can become aggressive tumors associated with distant metastasis, shortening survival. The survival of patients with large nonfunctional DP-NETs is known to be poor, but the overall contribution of DP-NETs to metastatic spread is poorly known. METHODS: The study population included patients with DP-NETs diagnosed after 1990 and followed in the MEN1 cohort of the Groupe d'étude des Tumeurs Endocrines (GTE). A multistate Markov piecewise constant intensities model was applied to separate the effects of prognostic factors on 1) metastasis, and 2) metastasis-free death or 3) death after appearance of metastases. RESULTS: Among the 603 patients included, 39 had metastasis at diagnosis of DP-NET, 50 developed metastases during follow-up, and 69 died. The Markov model showed that Zollinger-Ellison-related tumors (regardless of tumor size and thymic tumor pejorative impact), large tumors over 2 cm, and age over 40 years were independently associated with an increased risk of metastases. Men, patients over 40 years old and patients with tumors larger than 2 cm, also had an increased risk of death once metastasis appeared. CONCLUSIONS: DP-NETs of 2 cm in size or more, regardless of the associated secretion, should be removed to prevent metastasis and increase survival. Surgery for gastrinoma remains debatable.


Assuntos
Neoplasias Duodenais/patologia , Neoplasia Endócrina Múltipla Tipo 1/secundário , Neoplasias Pancreáticas/patologia , Adulto , Estudos de Coortes , Neoplasias Duodenais/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/mortalidade , Neoplasias Pancreáticas/mortalidade , Taxa de Sobrevida
11.
Eur J Nucl Med Mol Imaging ; 47(10): 2358-2371, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32062681

RESUMO

PURPOSE: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177Lu-DOTATOC or 177Lu-DOTATATE (LAN-peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs). METHODS: International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN-PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment. RESULTS: Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN-PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN-PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported. CONCLUSION: Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures. TRIAL REGISTRATION: Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578.


Assuntos
Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/radioterapia , Octreotida/efeitos adversos , Peptídeos Cíclicos , Radioisótopos , Receptores de Peptídeos , Estudos Retrospectivos , Somatostatina/análogos & derivados , Resultado do Tratamento
12.
Eur J Nucl Med Mol Imaging ; 47(10): 2372-2382, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32123969

RESUMO

PURPOSE: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. METHODS: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. RESULTS: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. CONCLUSIONS: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.


Assuntos
Neoplasias Hepáticas , Tumores Neuroendócrinos , Compostos Organometálicos , Fosfatase Alcalina , Humanos , Neoplasias Hepáticas/radioterapia , Tumores Neuroendócrinos/radioterapia , Octreotida/efeitos adversos , Compostos Organometálicos/uso terapêutico , Resultado do Tratamento
13.
Neuroendocrinology ; 110(5): 404-412, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31430756

RESUMO

BACKGROUND: Neuroendocrine carcinomas (NECs) of the digestive tract are rare and aggressive tumours. In localised disease the treatment is surgery. Based on expert consensus, international guidelines recommend the administration of adjuvant chemotherapy combining etoposide and platinum derivatives, justified by the high risk of metastatic relapse. However, no clinical study has proven the benefit of neoadjuvant or adjuvant chemotherapy. OBJECTIVES: We aimed to evaluate the effect of neoadjuvant +/- adjuvant and adjuvant therapy in this indication. METHODS: We performed a retrospective observational French study to evaluate overall survival (OS) and disease-free survival (DFS), prognostic factors for survival, and chemotherapy toxicity. RESULTS: Seventy-three patients had surgical resection of a localised digestive NEC between January 1, 2000 and December 31, 2016. The majority of patients presented colorectal (35%) tumours and the median Ki-67 value was 70%. Forty-three patients received chemotherapy, either perioperative (neoadjuvant +/- adjuvant) or adjuvant. The median OS and DFS for the whole population was 24 and 9 months, respectively. The median OS and DFS for patients receiving chemotherapy was 62 and 13 months, respectively. Positive postoperative node status and Ki-67 ≥80% had a negative prognostic impact on OS and DFS. Administration of chemotherapy had a positive prognostic impact on OS and DFS. Sixteen grade 3/4 toxicities were reported without toxic death. CONCLUSIONS: Our results suggest a positive effect on survival of chemotherapy in resected digestive NECs, but further studies are needed to confirm these results.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/mortalidade , Neoplasias do Sistema Digestório/tratamento farmacológico , Neoplasias do Sistema Digestório/mortalidade , Avaliação de Resultados em Cuidados de Saúde , Adulto , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Neuroendócrino/cirurgia , Quimioterapia Adjuvante , Neoplasias do Sistema Digestório/cirurgia , Feminino , França , Humanos , Antígeno Ki-67 , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
14.
J Med Genet ; 56(8): 513-520, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30877234

RESUMO

BACKGROUND: Knowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS). METHODS: We developed a custom multigene panel, which includes 17 PPGL genes and is compatible with both germline and tumour DNA screening. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours. RESULTS: In the retrospective cohort, the sensitivity of the NGS assay was evaluated at 100% for point and indels mutations and 86% for large rearrangements. The mutation rate was re-evaluated from 65% (132/202) to 78% (156/201) after NGS analysis. In the prospective cohort, NGS detected not only germline and somatic mutations but also co-occurring variants and mosaicism. A mutation was identified in 74% of patients for whom both germline and tumour DNA were available. CONCLUSION: The analysis of 824 DNAs from patients with PPGL demonstrated that NGS assay significantly improves the performances of PPGL genetic testing compared with conventional methods, increasing the rate of identified mutations and identifying rare genetic mechanisms.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Paraganglioma/genética , Feocromocitoma/genética , Alelos , Estudos de Associação Genética , Testes Genéticos/métodos , Testes Genéticos/normas , Variação Genética , Genótipo , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Análise de Sequência de DNA
15.
Ann Surg ; 270(1): 165-171, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29557879

RESUMO

OBJECTIVE: The primary endpoint was to analyze the predictive factors of lymph node involvement (LN+). BACKGROUND: Indications for additional right hemicolectomy (RHC) with lymph node (LN) resection after appendectomy for appendix neuroendocrine tumor (A-NET) remain controversial, especially for tumors between 1 and 2 cm in size. METHODS: National study including all patients with nonmetastatic A-NET diagnosed after January, 2010 in France. RESULTS: In all, 403 patients were included. A-NETs were: within tip (67%), body (24%) or base (9%) of the appendix; tumor size was < 1 cm (62%), 1 to 2 cm (30%), or >2 cm (8%); grade 1 (91%); mesoappendix involvement 3 mm (5%); lymphovascular (15%) or perineural (24%) invasion; and positive resection margin (8%). According to the European NeuroEndocrine Tumor Society (ENETS) recommendations, 85 patients (21%) should have undergone RHC. The agreement between ENETS guidelines and the multidisciplinary tumor board for complementary RHC was 89%. In all, 100 (25%) patients underwent RHC with LN resection, 26 of whom had LN+. Tumor size (best cut-off at 1.95 cm), lymphovascular and perineural invasion, and pT classifications were associated with LN+. Among the 44 patients who underwent RHC for a tumor of 1 to 2 cm in size, 8 (18%) had LN+. No predictive factor of LN+ (base, resection margins, grade, mesoappendix, lymphovascular, perineural involvement) was found in this subgroup of patients. CONCLUSIONS: In the largest study using the latest pathological criteria for completion RHC in A-NET, a quarter of patients had residual tumor. Further studies are warranted to demonstrate the survival impact of RHC in this setting.


Assuntos
Apendicectomia , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/cirurgia , Colectomia , Linfonodos/patologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
16.
BMC Cancer ; 19(1): 66, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642293

RESUMO

BACKGROUND: Lanreotide depot/autogel antitumor activity in intestinal/pancreatic neuroendocrine tumors (NETs) was demonstrated in the phase-3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) versus placebo. METHODS: During CLARINET, patients with metastatic intestinal/pancreatic NETs received lanreotide depot/autogel 120 mg or placebo every 4 weeks for 96 weeks. Imaging data (response evaluation criteria in solid tumors [RECIST] v1.0, centrally reviewed) were re-evaluated in this post hoc analysis of tumor growth rate (TGR) in NETs. TGR (%/month) was calculated from two imaging scans during relevant periods: pre-treatment (TGR0); 12-24 weeks before randomization versus baseline; each treatment visit versus baseline (TGRTx-0); between consecutive treatment visits (TGRTx-Tx). To assess TGR as a measure of prognosis, PFS was compared for TGR0 subgroups stratified by optimum TGR0 cut-off; a multivariate analysis was conducted to identify prognostic factors for PFS. RESULTS: TGR0 revealed tumors growing during pre-treatment (median [interquartile range] TGR0: lanreotide 2.1%/month [0.2; 6.1]; placebo 2.7%/month [0.15; 6.8]), contrary to RECIST status. TGR was significantly reduced by 12 weeks with lanreotide versus placebo (difference in least-square mean TGR0-12 of - 2.9 [- 5.1, - 0.8], p = 0.008), a difference that was maintained at most subsequent visits. TGR0 > 4%/month had greater risk of progression/death than ≤4%/month (hazard ratio 4.1; [95% CI 2.5-6.5]; p < 0.001); multivariate analysis revealed lanreotide treatment, progression at baseline, TGR0, hepatic tumor load, and primary tumor type were independently associated with PFS. CONCLUSIONS: TGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity. TRIAL REGISTRATION: Retrospective registration, 18 July 2006; EudraCT: 2005-004904-35; ClinicalTrials.gov: NCT00353496 .


Assuntos
Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Carga Tumoral
17.
Neuroendocrinology ; 108(1): 54-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30153658

RESUMO

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1 to G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinomas (NEC). Recently, a new subgroup of well-differentiated high-grade pancreatic tumors (NET G3) has been defined. The GEP NEN G3 group consisting of both NEC and NET G3 has recently been shown to be a quite heterogeneous patient group concerning prognosis and treatment benefit, depending on factors such as the primary tumor site, differentiation, proliferation rate, and molecular alterations. In this review we discuss the existing data on diagnostics, treatment, and biomarkers in this patient group, the unmet needs, and the future perspectives.


Assuntos
Neoplasias Gastrointestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Biomarcadores/metabolismo , Pesquisa Biomédica/tendências , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo
18.
Neuroendocrinology ; 108(1): 7-17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30248673

RESUMO

Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future.


Assuntos
Pesquisa Biomédica/tendências , Tumor Carcinoide , Neoplasias Pulmonares , Tumores Neuroendócrinos , Tumor Carcinoide/classificação , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/tratamento farmacológico , Humanos , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/tratamento farmacológico , Prognóstico
19.
Eur Radiol ; 29(10): 5655-5663, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30877460

RESUMO

OBJECTIVES: To evaluate post-ablation MRI for the detection of incompletely treated spinal osseous metastases (SOM) after cryoablation and to propose a post-ablation imaging classification. METHODS: After IRB consent, all patients treated with cryoablation of SOM between 2011 and 2017 having at least 1-year minimum follow-up and a spine MRI within 4 months after cryoablation were retrospectively included. A classification of MRI images into four types was set up. The primary endpoint of our study was to assess the diagnostic performance of the post-ablation MRI. The secondary endpoints were the 1-year complete treatment rate (CTR) and complications. RESULTS: Fifty-four SOMs in 39 patients were evaluated. Post-ablation MRI was performed with a median delay of 25 days after cryoablation. Images were evaluated by two independent readers according to the pre-established image classification. Sensitivity and specificity for the detection of residual tumor were 77.3% (95%CI = 62.2-88.5) and 85.9% (95%CI = 75.0-93.4), respectively. Types I, II, III, and IV of the classification were associated with a 1-year complete treatment in 100%, 83.3%, 35.7%, and 10% of cases, respectively. The 1-year CTR was 59.3% for all 54 metastases, and 95.8% for metastases measuring less than 25 mm and at least 2 mm or more away from the spinal canal. Two grade 3 and two grade 2 adverse events according to the CTCAE were reported. CONCLUSIONS: MRI after cryoablation is useful for the evaluation of the ablation efficacy. The classification of post-cryoablation MRI provides reliable clues for the prediction of complete treatment at 1 year. KEY POINTS: • MRI performed 25 days after cryoablation is useful to evaluate the efficacy. • The proposed classification provides a reliable clue for complete cryoablation. • Percutaneous cryoablation of spinal metastases is highly effective for lesions less than 25 mm in diameter and of at least 2 mm away from the spinal canal.


Assuntos
Vértebras Cervicais , Criocirurgia/métodos , Detecção Precoce de Câncer/métodos , Vértebras Lombares , Imageamento por Ressonância Magnética/métodos , Neoplasias da Coluna Vertebral/diagnóstico , Vértebras Torácicas , Adulto , Idoso , Tomografia Computadorizada de Feixe Cônico , Feminino , Fluoroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/cirurgia , Cirurgia Assistida por Computador/métodos , Resultado do Tratamento , Adulto Jovem
20.
Ann Surg ; 268(1): 158-164, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28263205

RESUMO

OBJECTIVE: To report long-term follow-up of patients with multiple endocrine neoplasia type 1 (MEN1) and nonfunctioning pancreatic neuroendocrine tumors (NF-PET). BACKGROUND: Pancreaticoduodenal tumors occur in almost all patients with MEN1 and are a major cause of death. The natural history and clinical outcome are poorly defined, and management is still controversial for small NF-PET. METHODS: Clinical outcome and tumor progression were analyzed in 46 patients with MEN1 with 2 cm or smaller NF-PET who did not have surgery at the time of initial diagnosis. Survival data were analyzed using the Kaplan-Meier method. RESULTS: Forty-six patients with MEN1 were followed prospectively for 10.7 ±â€Š4.2 (mean ±â€Šstandard deviation) years. One patient was lost to follow-up and 1 died from a cause unrelated to MEN1. Twenty-eight patients had stable disease and 16 showed significant progression of pancreaticoduodenal involvement, indicated by increase in size or number of tumors, development of a hypersecretion syndrome, need for surgery (7 patients), and death from metastatic NF-PET (1 patient). The mean event-free survival was 13.9 ±â€Š1.1 years after NF-PET diagnosis. At last follow-up, none of the living patients who had undergone surgery or follow-up had evidence of metastases on imaging studies. CONCLUSIONS: Our study shows that conservative management for patients with MEN1 with NF-PET of 2 cm or smaller is associated with a low risk of disease-specific mortality. The decision to recommend surgery to prevent tumor spread should be balanced with operative mortality and morbidity, and patients should be informed about the risk-benefit ratio of conservative versus aggressive management when the NF-PET represents an intermediate risk.


Assuntos
Tratamento Conservador , Neoplasia Endócrina Múltipla Tipo 1/terapia , Neoplasias Pancreáticas/terapia , Adulto , Tomada de Decisão Clínica , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/mortalidade , Neoplasias Pancreáticas/mortalidade , Estudos Prospectivos , Resultado do Tratamento
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