Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial

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

Clinical Characteristics and Diagnostic Criteria of Maturity-Onset Diabetes Of The Young (MODY) due to Molecular Anomalies of the HNF1A Gene

Context: The diagnosis of maturity-onset diabetes of the young type 3 (MODY3), associated with HNF1A molecular abnormalities, is often missed.Objective: The objective of the study was to describe the phenotypes of a large series of MODY3 patients and to reassess parameters that may improve its diagnosis. Design, Setting, and Patients: This retrospective multicenter study included 487 unrelated patients referred because of suspicion of MODY3. Genetic analysis identified 196 MODY3 and 283 non-MODY3 cases. Criteria associated with MODY3 were assessed by multivariate analysis. The capacity of the model to predict MODY3 diagnosis was assessed by the area under the receiver-operating characteristic curve and was further validated in an independent sample of 851 patients (165 MODY3 and 686 non-MODY3). Results: In the MODY3 patients, diabetes was revealed by clinical symptoms in 25% of the cases and was diagnosed by screening in the others. Age at diagnosis of diabetes was more than 25 yr in 40% of the MODY3 patients. There was considerable variability and overlap of all assessed parameters in MODY3 and non-MODY3 patients. The best predictive model was based on criteria available at diagnosis of diabetes, including age, body mass index, number of affected generations, presence of diabetes symptoms, and geographical origin. The area under the curve of the receiver-operating characteristic analysis was 0.81. When sensitivity was set to 90%, specificity was 49%. Conclusions: Differential diagnosis between MODY3 and early-onset type 2 diabetes remains difficult. Whether the proposed model will improve the pick-up rate of MODY3 diagnosis needs to be confirmed in independent populations

Traitement de l'infertilité féminine par administration pulsatile de GNRH (10 ans d'expérience au CHU d'Angers)

But : L objectif de cette étude est d évaluer l efficacité de la GnRH pulsatile en termes de conception chez des patientes atteintes d infertilité supra-hypophysaire. Population et méthodes : Il s agit d une étude rétrospective réalisée sur 10 ans au CHU d Angers. Résultats : Nous avons étudié l induction de l ovulation chez 36 patientes, soit 192 cycles de GnRH pulsatile au total. La population étudiée présentait des antécédents de troubles du comportement alimentaire pour 72,9% des patientes. Le traitement a été administré par voie sous cutanée et intra veineuse dans respectivement 87% et 13% des cycles. Le taux de grossesse par cycle ovulatoire a été de 24,8% et le taux cumulé global de grossesse à 6 mois a été de 81,6%. Le taux d ovulation par cycle s élevait à 73,4% des cycles. Le taux de fausse couche et de grossesse multiple par cycle ont été respectivement de 14,3% et de 2,85%. La durée moyenne de la grossesse a été de 39SA plus ou moins 3 jours, la prise de poids moyenne pendant la grossesse a été de 12,1kg et le poids de naissance moyen des nouveau-nés a été de 3066g plus ou moins 339g. Aucun cas d hyperstimulation ovarienne n a été décrit. On a observé l apparition d inflammations localisées au point d injection, de kystes ovariens fonctionnels et de phénomènes allergiques dans respectivement 12,5%, 10,4% et 0,52% des cycles.Conclusion : Le traitement par administration de GnRH pulsatile est efficace sur l obtention d une grossesse avec peu d effets indésirables, un faible risque de grossesse multiple et pour un coût limité. L évolution des grossesses induites est majoritairement favorable.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

The French COMETE-Cancer network for adrenal cancer: 10 years of activity as part of a national plan for clinical care of rare cancers

International audienceP826The French COMETE-Cancer network for adrenal cancer: 10 years of activity as part of a national plan for clinical care of rare cancersIntroductionThe French National Institute of Cancer (INCa) launched supported by the Ministry of Health in 2008 a program for the recognition of national networks for the management of rare cancers. Among the 23 selected networks COMETECancer was recognized by INCa in 2009 for Adrenocortical carcinoma (ACC) and malignant pheochromocytoma/paraganglioma (MPP). At that time 60–120 new ACC/year and 30 new MPP/year were expected at the national level.AimTo describe the general activities of COMETE-cancer after 10-years of activity.Materials and methodsINCa list 7 tasks for the national rare cancer networks: 1) Expertise: double reading of tumor samples, Referral National Multisciplinary Staff (RNMS); 2) Care practice: national best practice guidelines release; 3) Referral: patient access to highly specialized/innovative treatments (clinical trial); 4) Observation: exhaustive recording of national cases in registries; 5) Clinical and translationalresearch; 6) Healthcare professional training; 7) Role of patient associations. TheFrench COMETE-K network is coordinated by two-sites Centers (Cochin andGustave Roussy). Ten Regional Experts Centers have been recognized for anational geographical coverage.ResultsA double reading is done in about 200 cases of ACC/MPP tumor samples/year. A RNMS is organized twice a month (web based system): about 170 ACC and MPP patients/year are discussed. The coverage rate of ‘new’ patients reviewed in RNMS/‘estimated’ total number cases was 68%. The consistency between treatment proposed in RNMS and treatment administered was of 84%. Since2010, 958 ACC and 384 MPP have been entered in the ENSAT database. Two National best practice guidelines for ACC/MPP were released. About 70 ACC/MPP have been referred to the COMETE-Cancer centers for highly specialized and innovative treatment (phase II-III trial, radiofrequency/cryotherapy, liver chimioembolisation). COMETE-Cancer participated in two international trials (ADIUVO in ACC and FIRSTMAPP in MPP) and more than 20 translational studies. Every year more than 500 healthcare professional (student, endocrinologists, surgeons, pathologist, oncologists) are trained. Moreover, it strongly collaborates with the patients ‘Association Surre´nale’ by writing specific documents on the clinical ACC/MPP management.ConclusionsCOMETE-cancer has led to a homogenous national organization for clinical care of ACC and MPP. The RNMS proved to be very efficient for that. Links with the ENSAT, ENDO-ERN and EURACAN networks will allow further progress at the European level.DOI: 10.1530/endoabs.63.P82

Second-Line Treatment and Prognostic Factors in Neuroendocrine Carcinoma.

International audienceNeuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of Rb 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 multicenter study. NEC patients treated in 2L and further, with tissue samples available were included. Rb status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61) 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%), gastro-enteropancreatic (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 Rb status. Thoracic 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 ≥q 3 months after first-line platinum-etoposide, 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. Rb status does not provide prognostic information in this setting