Marianne Pavel
Charité
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Featured researches published by Marianne Pavel.
The New England Journal of Medicine | 2011
James C. Yao; Manisha H. Shah; Tetsuhide Ito; Catherine Lombard Bohas; Edward M. Wolin; Eric Van Cutsem; Timothy J. Hobday; Takuji Okusaka; Jaume Capdevila; Elisabeth G.E. de Vries; Paola Tomassetti; Marianne Pavel; Sakina Hoosen; Tomas Haas; Jeremie Lincy; David Lebwohl; Kjell Öberg
BACKGROUND Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).
The Lancet | 2011
Marianne Pavel; John D. Hainsworth; Eric Baudin; Marc Peeters; Dieter Hörsch; Robert Winkler; Judith Klimovsky; David Lebwohl; Valentine Jehl; Edward M. Wolin; Kjell Öberg; Eric Van Cutsem; James C. Yao
BACKGROUND Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). METHODS We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov, number NCT00412061. FINDINGS 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7-21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4-14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59-1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62%vs 14%), rash (37%vs 12%), fatigue (31%vs 23%), and diarrhoea (27%vs 16%). INTERPRETATION Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. FUNDING Novartis Pharmaceuticals.
The New England Journal of Medicine | 2014
Martyn Caplin; Marianne Pavel; Jarosław B. Ćwikła; Alexandria T. Phan; Markus Raderer; Eva Sedlackova; Guillaume Cadiot; Edward M. Wolin; Jaume Capdevila; Lucy Wall; Guido Rindi; Alison Langley; Séverine Martinez; Joëlle Blumberg; Philippe Ruszniewski
BACKGROUND Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).
Neuroendocrinology | 2012
Marianne Pavel; Eric Baudin; Anne Couvelard; Eric P. Krenning; Kjell Öberg; Thomas Steinmüller; Martin Anlauf; Bertram Wiedenmann; Ramon Salazar
ENETS Consensus Guidelines for the Management of Patients with Liver and Other Distant Metastases from Neuroendocrine Neoplasms of Foregut, Midgut, Hindgut, and Unknown Primary
Alimentary Pharmacology & Therapeutics | 2009
Irvin M. Modlin; Marianne Pavel; Mark Kidd; Bjorn I. Gustafsson
Background The discovery of somatostatin (SST) and the synthesis of a variety of analogues constituted a major therapeutic advance in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours (GEP‐NETs). They currently provide the most efficient treatment to achieve symptomatic relief and have recently been demonstrated to inhibit tumour growth.
The New England Journal of Medicine | 2017
Jonathan R. Strosberg; G. El-Haddad; Edward M. Wolin; Andrew Eugene Hendifar; James C. Yao; Beth Chasen; Erik Mittra; Pamela L. Kunz; Matthew H. Kulke; Heather A. Jacene; David L. Bushnell; Thomas M. O'Dorisio; Richard P. Baum; H. R. Kulkarni; Martyn Caplin; R. Lebtahi; Timothy J. Hobday; E. Delpassand; E. Van Cutsem; Al B. Benson; R. Srirajaskanthan; Marianne Pavel; J. Mora; Jordan Berlin; Enrique Grande; Nick Reed; E. Seregni; Kjell Öberg; M. Lopera Sierra; P. Santoro
Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first‐line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium‐177 (177Lu)–Dotatate in patients with advanced, progressive, somatostatin‐receptor–positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well‐differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu‐Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long‐acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu‐Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression‐free survival. Secondary end points included the objective response rate, overall survival, safety, and the side‐effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data‐cutoff date for the primary analysis, the estimated rate of progression‐free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu‐Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu‐Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu‐Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu‐Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu‐Dotatate resulted in markedly longer progression‐free survival and a significantly higher response rate than high‐dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu‐Dotatate group. (Funded by Advanced Accelerator Applications; NETTER‐1 ClinicalTrials.gov number, NCT01578239; EudraCT number 2011‐005049‐11.)
The Lancet | 2016
James C. Yao; Nicola Fazio; Simron Singh; Roberto Buzzoni; Carlo Carnaghi; Edward M. Wolin; Jiri Tomasek; Markus Raderer; Harald Lahner; Maurizio Voi; Lida Bubuteishvili Pacaud; Nicolas Rouyrre; C. Sachs; Juan W. Valle; Gianfranco Delle Fave; Eric Van Cutsem; Margot Tesselaar; Yasuhiro Shimada; Do Youn Oh; Jonathan R. Strosberg; Matthew H. Kulke; Marianne Pavel
BACKGROUND Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population. METHODS In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. FINDINGS Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0). INTERPRETATION Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract. FUNDING Novartis Pharmaceuticals Corporation.
Neuroendocrinology | 2008
Thomas Steinmüller; Reza Kianmanesh; Massimo Falconi; Aldo Scarpa; Babs G. Taal; Dik J. Kwekkeboom; José Manuel Lopes; Aurel Perren; George Nikou; James C. Yao; Gian Franco Delle Fave; Dermot O'Toole; Håkan Ahlman; Rudolf Arnold; Christoph J. Auernhammer; Martyn Caplin; Emanuel Christ; Anne Couvelard; Wouter W. de Herder; Barbro Eriksson; Diego Ferone; Peter E. Goretzki; David J. Gross; Rudolf Hyrdel; Robert T. Jensen; Gregory Kaltsas; Fahrettin Kelestimur; Günter Klöppel; Wolfram H. Knapp; Ulrich Knigge
a DRK Kliniken Westend, Berlin , Germany; b UFR Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, Hopital Louis Mourier, Colombes , France; c Medicine and Surgery, General Surgery Section, MED/18 – General Surgery and d Department of Pathology, University of Verona, Verona , Italy; e Netherlands Cancer Centre, Amsterdam , and f Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam , The Netherlands;
Neuroendocrinology | 2009
Günter Klöppel; Anne Couvelard; Aurel Perren; Paul Komminoth; Anne Marie McNicol; Ola Nilsson; Aldo Scarpa; Jean-Yves Scoazec; Bertram Wiedenmann; Mauro Papotti; Guido Rindi; Ursula Plöckinger; Göran Åkerström; Annibale Bruno; Rudolf Arnold; Emilio Bajetta; Jaroslava Barkmanova; Yuan Jia Chen; Frederico Costa; Joseph Davar; Wouter W. de Herder; Gianfranco Delle Fave; Barbro Eriksson; Massimo Falconi; Diego Ferone; David J. Gross; Ashley B. Grossman; Bjorn I. Gustafsson; Rudolf Hyrdel; Diana Ivan
ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification
Annals of Surgical Oncology | 2010
Irvin M. Modlin; Bjorn I. Gustafsson; Steven F. Moss; Marianne Pavel; Apostolos V. Tsolakis; Mark Kidd
BackgroundNeuroendocrine tumors (NETs) are a form of cancer that differ from other neoplasia in that they synthesize, store, and secrete peptides, e.g., chromogranin A (CgA) and amines. A critical issue is late diagnosis due to failure to identify symptoms or to establish the biochemical diagnosis. We review here the utility of CgA measurement in NETs and describe its biological role and the clinical value of its measurement.MethodsLiterature review and analysis of the utility of plasma/serum CgA measurements in NETs and other diseases.ResultsCgA is a member of the chromogranin family; its transcription and peptide processing are well characterized, but its precise function remains unknown. Levels are detectable in the circulation but vary substantially (~25%) depending on which assay is used. Serum and plasma measurements are concordant. CgA is elevated in ~90% of gut NETs and correlates with tumor burden and recurrence. Highest values are noted in ileal NETs and gastrointestinal NETs associated with multiple endocrine neoplasia type 1. Both functioning and nonfunctioning pancreatic NETs have elevated values. CgA is more frequently elevated in well-differentiated tumors compared to poorly differentiated NETs. Effective treatment is often associated with decrease in CgA levels. Proton pump inhibitors falsely increase CgA, but levels normalize with therapy cessation.ConclusionsCgA is currently the best available biomarker for the diagnosis of NETs. It is critical to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy. Measurement of plasma CgA is mandatory for the effective diagnosis and management of NET disease.