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1. Lactic acidosis together with GM-CSF and M-CSF induces human macrophages toward an inflammatory pro-tumor phenotype

Author

Laurence Preisser, Pedro Raro, Clément Adam, Pascale Pignon, Vincent Procaccio, Vincent Lavoué, Alain Morel, Philippe Descamps, Simon Blanchard, Cinzia Bocca, Valérie Seegers, Céline Beauvillain, Romuald Wernert, Judith Kouassi Nzoughet, Léa Paolini, Norbert Ifrah, Pascale Jeannin, Véronique Verrielle, Yves Delneste, Mario Campone, Véronique Catros, Louise-Marie Chevalier, Guy Lenaers, Guillaume Tcherkez, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), CHU Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Canberra, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), INCa-DGOS-Inserm_12558, Ministry of Health and the Institute for Health and Medical Research, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Immunologie et d'Allergologie [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Ressources Biologiques Santé (CRB Santé), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Australian National University (ANU), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), SIRIC ILIAD program (National Cancer Institute, Ministry of Health and the Institute for Health and Medical Research, INCa-DGOS-Inserm_12558)Ligue contre le Cancer (comitée du Maine et Loire, Angers, France) and the regional council of Pays de la Loire (Canceropole Grand-Ouest, projects PlasTICO and Concerto), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Innate immunity and Immunotherapy (CRCINA - Département INCIT - Equipe 7), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Stress Adaptation and Tumor Escape in breast cancer - SATE (CRCINA - Département ONCO - Equipe 8), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Blanchard, Simon, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID

Subjects
0301 basic medicine, Cancer Research, Chemokine, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Monocytes, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Tumor Cells, Cultured, medicine, Humans, cancer, Interleukin 8, Autocrine signalling, ComputingMilieux_MISCELLANEOUS, Ovarian Neoplasms, lactate, biology, Chemistry, Macrophage Colony-Stimulating Factor, Macrophages, Granulocyte-Macrophage Colony-Stimulating Factor, Cell Differentiation, GM-CSF, medicine.disease, M-CSF, 3. Good health, Interleukin 10, Phenotype, 030104 developmental biology, inflammation, 030220 oncology & carcinogenesis, Monocyte differentiation, Lactic acidosis, biology.protein, Cancer research, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Acidosis, Lactic, Female, medicine.symptom
Abstract

In established tumors, tumor-associated macrophages (TAM) orchestrate nonresolving cancer-related inflammation and produce mediators favoring tumor growth, metastasis, and angiogenesis. However, the factors conferring inflammatory and protumor properties on human macrophages remain largely unknown. Most solid tumors have high lactate content. We therefore analyzed the impact of lactate on human monocyte differentiation. We report that prolonged lactic acidosis induces the differentiation of monocytes into macrophages with a phenotype including protumor and inflammatory characteristics. These cells produce tumor growth factors, inflammatory cytokines, and chemokines as well as low amounts of IL10. These effects of lactate require its metabolism and are associated with hypoxia-inducible factor-1α stabilization. The expression of some lactate-induced genes is dependent on autocrine M-CSF consumption. Finally, TAMs with protumor and inflammatory characteristics (VEGFhigh CXCL8+ IL1β+) are found in solid ovarian tumors. These results show that tumor-derived lactate links the protumor features of TAMs with their inflammatory properties. Treatments that reduce tumor glycolysis or tumor-associated acidosis may help combat cancer.

Published
2020

2. Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer With Peritoneal Metastases (CYTO-CHIP study): A Propensity Score Analysis

Author

Frédéric Marchal, Jérémie H. Lefevre, François Quenet, Guillaume Piessen, Pierre-Emmanuel Bonnot, Patrick Rat, Pierre Meeus, Johan Gagnière, Bernard Meunier, Big-Renape Networks, J.M. Bereder, Catherine Arvieux, Simon Msika, Karine Abboud, Vahan Kepenekian, Diane Goéré, Nicolas Pirro, Michel Rivoire, Reza Kianmanesh, Olivier Glehen, Fregat, Marc Pocard, Evelyne Decullier, Romuald Wernert, Thomas Courvoisier, Guillaume Passot, Delphine Vaudoyer, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital Claude Huriez [Lille], CHU Lille, Pôle Information Médicale Evaluation Recherche (IMER), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Saint-Etienne, Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Gustave Roussy (IGR), Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Grenoble, Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service de Chirurgie Digestive, Cancérologique, Générale, Endocrinienne et Urgences (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Clermont-Ferrand, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Léon Bérard [Lyon], Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Université de Lorraine (UL), Hopital Louis Mourier - AP-HP [Colombes], Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), and CHU Saint-Antoine [APHP]

Subjects
Hyperthermia, Oncology, Male, Cancer Research, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Text mining, Stomach Neoplasms, Internal medicine, medicine, Humans, Prospective Studies, Neoplasm Metastasis, Prospective cohort study, Peritoneal Neoplasms, business.industry, Cancer, Cytoreduction Surgical Procedures, Hyperthermia, Induced, Middle Aged, medicine.disease, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Propensity score matching, 030211 gastroenterology & hepatology, Hyperthermic intraperitoneal chemotherapy, Female, business, Cytoreductive surgery
Abstract

PURPOSE Gastric cancer (GC) with peritoneal metastases (PMs) is a poor prognostic evolution. Cytoreductive surgery (CRS) yields promising results, but the impact of hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial. Here we aimed to compare outcomes between CRS-HIPEC versus CRS alone (CRSa) among patients with PMs from GC. PATIENTS AND METHODS From prospective databases, we identified 277 patients with PMs from GC who were treated with complete CRS with curative intent (no residual nodules > 2.5 mm) at 19 French centers from 1989 to 2014. Of these patients, 180 underwent CRS-HIPEC and 97 CRSa. Tumor burden was assessed using the peritoneal cancer index. A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used to assess the effect of HIPEC and account for confounding factors. RESULTS After IPTW adjustment, the groups were similar, except that median peritoneal cancer index remained higher in the CRS-HIPEC group (6 v 2; P = .003). CRS-HIPEC improved overall survival (OS) in both crude and IPTW models. Upon IPTW analysis, in CRS-HIPEC and CRSa groups, median OS was 18.8 versus 12.1 months, 3- and 5-year OS rates were 26.21% and 19.87% versus 10.82% and 6.43% (adjusted hazard ratio, 0.60; 95% CI, 0.42 to 0.86; P = .005), and 3- and 5-year recurrence-free survival rates were 20.40% and 17.05% versus 5.87% and 3.76% ( P = .001), respectively; the groups did not differ regarding 90-day mortality (7.4% v 10.1%, respectively; P = .820) or major complication rate (53.7% v 55.3%, respectively; P = .496). CONCLUSION Compared with CRSa, CRS-HIPEC improved OS and recurrence-free survival, without additional morbidity or mortality. When complete CRS is possible, CRS-HIPEC may be considered a valuable therapy for strictly selected patients with limited PMs from GC.

Published
2019

3. Mycolactone as Analgesic: Subcutaneous Bioavailability Parameters

Author

David Guilet, Estelle Marion, Pascal Richomme, Jean-Paul Saint André, Laurent Marsollier, Anne Croué, Dimitri Bréard, Priscille Brodin, Jérémie Babonneau, Marie-Line Reynaert, ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Substances d'Origine Naturelle et Analogues Structuraux (SONAS), Université d'Angers (UA), SFR UA 4207 QUAlité et SAnté du Végétal (QUASAV), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Ecole supérieure d'Agricultures d'Angers (ESA), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire d’Anatomie Pathologique [ICO, Angers] (Site Paul Papin), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, This work was supported by the region Pays de la Loire (Kalmos project), the Agence Nationale de Recherche (ANR-17-CE18-0001), the Institut Pasteur of Lille (granted to PB and M-LR), the Inserm Program ATIP avenir (granted to LM), the region Pays de la Loire (Kalmos project) and Angers University., ANR-17-CE18-0001,AT2R-TRAAK-BIOANALGESICS,Caractérisations moléculaires et cellulaires de voies de signalisation de la douleur: contrôle de la douleur dans l'ulcère de buruli comme source d'inspiration pour la conception rationnelle de nouveaux analgésiques puissants(2017), Bernardo, Elizabeth, Caractérisations moléculaires et cellulaires de voies de signalisation de la douleur: contrôle de la douleur dans l'ulcère de buruli comme source d'inspiration pour la conception rationnelle de nouveaux analgésiques puissants - - AT2R-TRAAK-BIOANALGESICS2017 - ANR-17-CE18-0001 - AAPG2017 - VALID, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-AGROCAMPUS OUEST-Ecole supérieure d'Agricultures d'Angers (ESA), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), ATIP AVENIR / ATOMycA (CRCINA - Département INCIT - Equipe 6), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut National de la Recherche Agronomique (INRA)-Ecole supérieure d'Agricultures d'Angers (ESA)-Université de Nantes (UN)-AGROCAMPUS OUEST-Université d'Angers (UA), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin)

Subjects
0301 basic medicine, Buruli ulcer, [SDV.CAN]Life Sciences [q-bio]/Cancer, mycolactone, Pharmacology, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, Subcutaneous injection, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, biological action, medicine, Pharmacology (medical), Mycolactone, Original Research, Mycobacterium ulcerans, biology, Toxin, lcsh:RM1-950, analgesia, Hypoesthesia, biology.organism_classification, medicine.disease, 3. Good health, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Nociception, chemistry, 030220 oncology & carcinogenesis, medicine.symptom, bioavailability, Panniculitis
Abstract

Jérémie Babonneau, Dimitri Bréard and Marie-Line Reynaert have contributed equally to this work. Priscille Brodin, Pascal Richomme and Laurent Marsollier are co-senior authors.; International audience; Mycobacterium ulcerans is the bacillus responsible for Buruli ulcer, an infectious disease and the third most important mycobacterial disease worldwide, after tuberculosis and leprosy. M. ulcerans infection is a type of panniculitis beginning mostly with a nodule or an oedema, which can progress to large ulcerative lesions. The lesions are caused by mycolactone, the polyketide toxin of M. ulcerans. Mycolactone plays a central role for host colonization as it has immunomodulatory and analgesic effects. On one hand, mycolactone induces analgesia by targeting type-2 angiotensin II receptors (AT 2 R), causing cellular hyperpolarization and neuron desensitization. Indeed, a single subcutaneous injection of mycolactone into the mouse footpad induces a long-lasting hypoesthesia up to 48 h. It was suggested that the long-lasting hypoesthesia may result from the persistence of a significant amount of mycolactone locally following its injection, which could be probably due to its slow elimination from tissues. To verify this hypothesis, we investigated the correlation between hypoesthesia and mycolactone bioavailability directly at the tissue level. Various quantities of mycolactone were then injected in mouse tissue and hypoesthesia was recorded with nociception assays over a period of 48 h. The hypoesthesia was maximal 6 h after the injection of 4 µg mycolactone. The basal state was reached 48 h after injection, which demonstrated the absence of nerve damage. Surprisingly, mycolactone levels decreased strongly during the first hours with a reduction of 70 and 90% after 4 and 10 h, respectively. Also, mycolactone did not diffuse in neighboring skin tissue and only poorly into the bloodstream upon direct injection. Nevertheless, the remaining amount was sufficient to induce hypoesthesia during 24 h. Our results thus demonstrate that intact mycolactone is rapidly eliminated and that very small amounts of mycolactone are sufficient to induce hypoesthesia. Taken together, our study points out that mycolactone ought to be considered as a promising analgesic.

Published
2019

4. Recommandations du GEFPICS pour la prise en charge des prélèvements dans le cadre du traitement néoadjuvant du cancer du sein

Author

Maran-Gonzalez, Aurélie, Franchet, Camille, Duprez-Paumier, Raphaelle, Antoine, Martine, Barlier, Catherine, Bécette, Véronique, Berghian, Anca, Blanc-Fournier, Cécile, Brabencova, Eva, Charafe-Jauffret, Emmanuelle, Chenard, Marie-Pierre, Dauplat, Marie-Mélanie, Delrée, Paul, Fleury, Clémence, Garbar, Christian, Ghnassia, Jean-Pierre, Haudebourg, Juliette, MacGrogan, Gaëtan, Mathieu, Marie-Christine, Michenet, Patrick, Penault-Llorca, Frédérique, Poulet, Bruno, Robin, Yves, Roger, Pascal, Russ, Elisabeth, Treilleux, Isabelle, Valent, Alexander, Verriele, Véronique, Vincent-Salomon, Anne, Arnould, Laurent, Lacroix-Triki, Magali, Institut du Cancer de Montpellier (ICM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Hôpital René HUGUENIN (Saint-Cloud), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jean Godinot [Reims], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de Hautepierre [Strasbourg], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Immuno-Régulation dans les Maladies Auto-Immunes Inflammatoires et le Cancer - EA 7509 (IRMAIC), Université de Reims Champagne-Ardenne (URCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Régional d'Orléans (CHRO), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Université de Montpellier (UM), Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Institut Curie [Paris], Université Lumière - Lyon 2 - UFR de Sciences économiques et de gestion (UL2 UFR SEG), Université Lumière - Lyon 2 (UL2), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Lille Nord de France (COMUE)-UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CRLCC Institut Claudius Regaud, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology Bratislava, NUT a RCH, Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service d'anatomo-pathologie, Centre Jean Perrin, Pathology Department, CRLCC Paul Strauss, Laboratoire d'Anatomo-Pathologie, Hôpital Pasteur [Nice] (CHU), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie, CHU Orléans, CRLCC Jean Perrin, Calculateurs Parallèles (CALCPAR), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-INRIA Rennes, Institut National de Recherche en Informatique et en Automatique (Inria), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Department of Tumor Biology, Institut Curie, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Neoplasm, Residual, Tissue sample, Recommandations, [SDV]Life Sciences [q-bio], Biopsy, Prélèvement, Breast Neoplasms, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Guidelines, Medical Records, Réponse pathologique, Specimen Handling, Breast cancer, Biomarkers, Tumor, Humans, Néoadjuvant, Breast, Cancer du sein, Microscopy, Sentinel Lymph Node Biopsy, Prognosis, Neoadjuvant Therapy, Tumor Burden, Treatment Outcome, Chemotherapy, Adjuvant, Female, France, Lymph Nodes, Drug Screening Assays, Antitumor, Pathological response
Abstract

International audience; Neoadjuvant therapy is an increasing treatment option in the management of breast cancer. The tumor response to neoadjuvant therapy, especially the pathological complete response, is a validated endpoint frequently used in clinical trials. However, there is still a lack of standardization for the surgical specimen management in the neoadjuvant setting. This leads to heterogeneity in the specimen handling and might lead to significant bias for the prognostic assessment of patients or in clinical trials. The GEFPICS group, composed of expert breast cancer pathologists, herein presents guidelines for the management of breast and axillary specimen before treatment (management of biopsy, items of the pathological report) and after neoadjuvant therapy (specimen handling, histological assessment of response, items of the pathological report and response grading systems).

Published
2018

5. Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial

Author

Jaafar Bennouna, Yves Becouarn, C. Lepere, for Prodige investigators, Gercor, Fédération Française de Cancérologie Digestive, Laurent Mineur, Gaël Deplanque, Aimery de Gramont, Louis Marie Dourthe, Ahmed Khalil, Joëlle Egreteau, Marine Hug de Larauze, Unicancer, Jean-Baptiste Bachet, Roger Faroux, Jérôme Desramé, Olivier Dupuis, S. Fratte, Jeremie Bez, Thierry André, Marc Ychou, François Ghiringhelli, Olivier Bouché, May Mabro, Julien Taieb, Dewi Vernerey, Marie Pierre Galais, Christophe Louvet, Jérôme Dauba, Sophie Paget-Bailly, Franck Bonnetain, Benoist Chibaudel, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut Sainte Catherine [Avignon], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Hôpital privé Jean Mermoz, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, CH Belfort-Montbéliard, Fédération Francophone de la Cancérologie Digestive, FFCD, Centre Hospitalier Layné, Institut Mutualiste de Montsouris (IMM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Clinique Victor Hugo, Institut Bergonié [Bordeaux], Hôpital Foch [Suresnes], Groupe Hospitalier Bretagne Sud (GHBS), Hôpital universitaire Robert Debré [Reims], Groupe Hospitalier Paris Saint-Joseph, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Clinique Sainte Anne [Strasbourg], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Tenon [AP-HP], Institut hospitalier Franco-Britannique [Levallois-Perret], Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), CHU Saint-Antoine [APHP], Groupe cooperateur multidisciplinaire en oncologie (GERCOR), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Inserm UMR 1098, Centre René Gauducheau - ICO, institut de Cancerologie de l'Ouest, Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Bergonié - CRLCC Bordeaux, centre hospitalier Bretagne sud, Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), CHU Pitié-Salpêtrière [APHP], and CHU Tenon [APHP]

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, Capecitabine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Clinical endpoint, medicine, education, education.field_of_study, Chemotherapy, business.industry, medicine.disease, 3. Good health, Oxaliplatin, 030104 developmental biology, Oncology, Fluorouracil, 030220 oncology & carcinogenesis, business, Adjuvant, medicine.drug
Abstract

Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data.

Published
2018

6. Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort

Author

Laurence Vanlemmens, Marc Debled, Christian Cailliot, Elisa Gobbini, Thomas Bachelot, Monia Ezzalfani, Christelle Jouannaud, Suzette Delaloge, Magali Lacroix-Triki, Anne Patsouris, Thierry Petit, Simone Mathoulin-Pélissier, Veronique Lorgis, William Jacot, Marie Ange Mouret-Reynier, Mathieu Robain, C. Lefeuvre-Plesse, Florence Dalenc, Audrey Lardy Cleaud, Etienne Brain, Christelle Levy, David Pérol, C. Courtinard, Véronique Diéras, Marianne Leheurteur, Lionel Uwer, Anthony Gonçalves, Jean Marc Ferrero, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute Curie, Centre Léon Bérard [Lyon], Institut Curie [Saint-Cloud], Service d'Oncologie Médicale, CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale supérieure d'architecture de Toulouse (ENSA Toulouse), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Department of Medical Oncology, CRLCC Eugène Marquis (CRLCC), Centre d'Investigation Clinique - Epidemiologie Clinique / Essais Cliniques Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Jean Godinot, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Département de biologie et pathologie médicales [Gustave Roussy], Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Haute Normandie-CRLCC Henri Becquerel, CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Center Oscar Lambret, CRLCC Oscar Lambret, Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie - Saint Cloud (ICSC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-UNICANCER

Subjects
Adult, Cancer Research, medicine.medical_specialty, Multivariate analysis, Time Factors, Receptor, ErbB-2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Triple Negative Breast Neoplasms, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cancer Survivors, Risk Factors, HER2, Internal medicine, polycyclic compounds, Overall survival, Biomarkers, Tumor, Medicine, Humans, 030212 general & internal medicine, Neoplasm Metastasis, skin and connective tissue diseases, Aged, Retrospective Studies, Subtypes, Aged, 80 and over, business.industry, Time trends, Hazard ratio, Middle Aged, Metastatic breast cancer, medicine.disease, Confidence interval, 3. Good health, Treatment Outcome, Oncology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Cohort, Observational study, Female, France, business, Receptors, Progesterone
Abstract

Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively).The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.

Published
2018

7. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial

Author

Nadine Houede, Claude Linassier, Philippe Beuzeboc, Paule Chinet-Charrot, Laura Faivre, Loic Mourey, Aude Flechon, Frank Priou, Gael Deplanque, Jean-Marc Ferrero, Jean-Louis Davin, Christine Theodore, Muriel Habibian, Brigitte Laguerre, Remy Delva, Anne-Laure Martin, Ivan Krakowski, Agnès Laplanche, Karim Fizazi, Frederic Rolland, Jean-Luc Labourey, Stéphane Culine, Jean-François Berdah, Gwenaelle Gravis, François Lesaunier, Isabelle Cojean-Zelek, Eric Legouffe, Alain Ravaud, Marjorie Baciuchka, Stéphane Oudard, Jean-Léon Lagrange, Institut Gustave Roussy (IGR), Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), CRLCC Paul Papin-CRLCC René Gauducheau, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Hôpital Foch [Suresnes], Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Hôpital privé Toulon Hyères : Sainte Marguerite, Hôpital de la Timone [CHU - APHM] (TIMONE), CRLCC Eugène Marquis (CRLCC), Centre Léon Bérard [Lyon], Hôpital Saint-André, Groupe Hospitalier Diaconesses Croix Saint-Simon, Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Limoges, CRLCC Henri Becquerel, ONCOGARD - NIMES, Institut de Cancérologie du GARD (Instit Cancéro - GARD), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Hôpital Saint-Joseph, Institut Curie, Institut Sainte Catherine [Avignon], UNICANCER [Paris], Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut Curie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Université Côte d'Azur (UCA)-UNICANCER, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée)

Subjects
Male, medicine.medical_specialty, Maximum Tolerated Dose, Population, 030232 urology & nephrology, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Docetaxel, Kaplan-Meier Estimate, Disease-Free Survival, Drug Administration Schedule, Androgen deprivation therapy, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Neoplasm Invasiveness, education, Aged, Neoplasm Staging, Proportional Hazards Models, education.field_of_study, Dose-Response Relationship, Drug, business.industry, Standard treatment, Goserelin, Prostatic Neoplasms, Cancer, Androgen Antagonists, Middle Aged, Prostate-Specific Antigen, medicine.disease, Survival Analysis, 3. Good health, Surgery, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Estramustine, Taxoids, France, Neoplasm Recurrence, Local, business, Follow-Up Studies, medicine.drug
Abstract

International audience; BACKGROUND:Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer.METHODS:We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731.FINDINGS:We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths.INTERPRETATION:Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival.FUNDING:Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.

Published
2015

8. Radiation plus docetaxel and cisplatin in locally advanced pancreatic carcinoma: A non-comparative randomized phase II trial

Author

Frédéric Viret, Carmen Llacer, Marc Giovannini, Antoine Adenis, Thierry Conroy, Valérie Boige, Didier Peiffert, Michel Ducreux, Moncef Abbas, Beata Juzyna, Charlotte Baey, Jean-Pierre Pignon, Françoise Mornex, Patrice Cellier, Jaafar Bennouna, Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CRLCC Val d'Aurelle - Paul Lamarque, CRLCC René Gauducheau, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Department of Radiation Oncology, Centre Hospitalier Universitaire Lyon Sud, Pierre Benite, France, Hospices Civils de Lyon (HCL), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Centre Oscar Lambret [Lille], Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), and Université Lille Nord de France (COMUE)-UNICANCER

Subjects
Male, Oncology, medicine.medical_treatment, MESH: Taxoids, Phases of clinical research, Docetaxel, Gastroenterology, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, 030212 general & internal medicine, MESH: Chemoradiotherapy, MESH: Treatment Outcome, MESH: Aged, MESH: Middle Aged, Chemoradiotherapy, Middle Aged, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, MESH: Young Adult, MESH: Survival Analysis, 030220 oncology & carcinogenesis, Female, Taxoids, Fluorouracil, MESH: Pancreatic Neoplasms, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Antineoplastic Agents, Radio-chemotherapy, MESH: Drug Administration Schedule, Drug Administration Schedule, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Aged, MESH: Adolescent, Cisplatin, MESH: Humans, Hepatology, business.industry, MESH: Adult, Survival Analysis, MESH: Male, Confidence interval, Pancreatic Neoplasms, Radiation therapy, Regimen, MESH: Cisplatin, MESH: Antineoplastic Agents, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Pancreatic carcinoma, business, MESH: Female, MESH: Fluorouracil
Abstract

Background We performed a randomized, non-comparative phase II study evaluating docetaxel in combination with either daily continuous (protracted IV) 5-fluorouracil or cisplatin administered weekly, concurrent to radiotherapy in the treatment of locally advanced pancreatic carcinoma. Results of the docetaxel plus cisplatin regimen are reported. Methods Forty chemotherapy-naive patients with locally advanced pancreatic carcinoma were randomly assigned to receive 5-fluorouracil and docetaxel or docetaxel 20 mg/m2 and cisplatin 20 mg/m2/week, plus concurrent radiotherapy for 6 weeks. The radiation dose to the primary tumour was 54 Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate. Results 51 patients from 7 centres were included in the docetaxel–cisplatin treatment group. Six-month non-progression rate was 39% (95% confidence interval: 26–53). Median overall survival was 9.6 months (95% confidence interval: 2.4–60.7); 6 complete and 8 partial responses were obtained. Six patients survived more than 2 years after their inclusion in the trial. Grade ≥3 toxicity was reported in 63% of patients; no treatment-related death occurred. Severe toxicities were mainly anorexia (22%), vomiting (20%) and fatigue (24%). Conclusions Despite inadequate efficacy according to the main end point, this regimen gave a satisfactory rate of objective response (27%) with tolerable toxicity.

Published
2014

9. Combining gemcitabine, cisplatin, and ifosfamide (GIP) is active in patients with relapsed metastatic germ-cell tumors (GCT): a prospective multicenter GETUG phase II trial

Author

Lionnel Geoffrois, Remy Delva, N. Houede, Frederic Rolland, Agnès Laplanche, J.-C. Eymard, B. Laguerre, Aude Flechon, Karim Fizazi, Stéphane Culine, D. Burcoveanu, G. Gravis, Christine Chevreau, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Léon Bérard [Lyon], Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Institut Claudius Regaud, CRLCC Institut Claudius Regaud, CRLCC Eugène Marquis (CRLCC), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), CRLCC Jean Godinot, CRLCC René Gauducheau, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Institut Bergonié - CRLCC Bordeaux, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Bergonié [Bordeaux], Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Male, Oncology, 030232 urology & nephrology, Salvage therapy, Kaplan-Meier Estimate, Deoxycytidine, Gastroenterology, Testicular Neoplasms/*drug therapy/mortality/pathology, 0302 clinical medicine, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Ifosfamide, Hematology, Middle Aged, Neoplasms, Germ Cell and Embryonal, Ifosfamide/administration & dosage, Chemotherapy regimen, 3. Good health, Treatment Outcome, Germ Cell and Embryonal/*drug therapy/mortality/secondary, Lymphatic Metastasis, 030220 oncology & carcinogenesis, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Drug Administration Schedule, Young Adult, 03 medical and health sciences, Testicular Neoplasms, Internal medicine, Deoxycytidine/administration & dosage/analogs & derivatives, medicine, Local/*drug therapy, Humans, Antineoplastic Combined Chemotherapy Protocols/*therapeutic use, Progression-free survival, Survival rate, Salvage Therapy, business.industry, medicine.disease, Gemcitabine, Regimen, Neoplasm Recurrence, Cisplatin, Neoplasm Recurrence, Local, business, Cisplatin/administration & dosage, Febrile neutropenia
Abstract

International audience; BACKGROUND: The standard treatment of patients with metastatic germ-cell tumor (GCT) relapsing after first-line chemotherapy is based on a cisplatin and ifosfamide-containing three-drug regimen, which usually yields a complete response (CR) rate \textless50%. As gemcitabine consistently displayed activity in patients with advanced GCT and as synergy with cisplatin was reported, we integrated this drug into the salvage triplet regimen and assessed its activity in this phase II study. PATIENTS AND METHODS: The GIP regimen consisted in gemcitabine 1000 mg/m(2) day 1 and 5, ifosfamide 1200 mg/m(2)/day day 1-5, cisplatin 20 mg/m(2)/day day 1-5, and granulocyte colony-stimulating factor 263 mug/day day 7-15, repeated every 3 weeks for four cycles. Eligibility criteria were that patients had favorable prognostic factors to conventional-dose salvage chemotherapy including a testis primary tumor and a previous CR to first-line chemotherapy for metastatic disease. The primary end point was the CR rate and a two-stage Simon design was used. RESULTS: Thirty-seven patients were accrued and 29 (78%) achieved a favorable response, including a CR in 20 (54%) and a partial response with normalization of tumor markers (PRm-) in 9 (24%). With a median follow-up of 53 months (13-81), the 2-year overall survival rate is 73% (57%-84%) and the continuous progression-free survival rate is 51% (35%-66%). Myelosuppression was the main toxicity including febrile neutropenia in 8 (22%) patients and 18 (50%) cases required platelet infusion. No grade 3 and 4 peripheral neurotoxicity or renal toxicity occurred. Two patients died of treatment-related toxicity, one of them with cancer progression. CONCLUSION: In a multicenter context, four cycles of the GIP regimen achieved a high CR rate in patients with relapsed testicular GCT. The GIP regimen avoided severe neurotoxicity and yielded a high survival rate. CLINICAL TRIAL NUMBER: NCT00127049.

Published
2014

10. Significant effect of VEGFA polymorphisms on the clinical outcome of metastatic colorectal cancer patients treated with FOLFIRI-cetuximab

Author

M. Boisdron-Celle, Yves Gruel, Gilles Paintaud, Jérôme Rollin, Nicolas Azzopardi, Thierry Lecomte, Hervé Watier, Alain Morel, Valérie Gouilleux-Gruart, Audrey Payancé, Erick Gamelin, LAB'URBA (LAB'URBA), Université Paris-Est Marne-la-Vallée (UPEM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Développement normal et pathologique des lymphocytes et signalisation, Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Oppelia, Laboratoire d'Oncopharmacologie (Département de Pharmacogénétique), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Azzopardi, Nicolas

Subjects
Oncology, Male, Vascular Endothelial Growth Factor A, Colorectal cancer, Leucovorin, Bioinformatics, Antineoplastic Combined Chemotherapy Protocols, cetuximab, Neoplasm Metastasis, ComputingMilieux_MISCELLANEOUS, Cetuximab, 3. Good health, Vascular endothelial growth factor A, Treatment Outcome, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, FOLFIRI, Molecular Medicine, Female, Fluorouracil, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Colorectal Neoplasms, medicine.drug, SNPs, VEGFA, medicine.medical_specialty, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Single-nucleotide polymorphism, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Lower risk, Disease-Free Survival, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Internal medicine, Genetics, medicine, Humans, Retrospective Studies, Pharmacology, Polymorphism, Genetic, business.industry, Haplotype, biomarkers, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, digestive system diseases, Regimen, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Camptothecin, business
Abstract

International audience; Aim: The efficacy of a cetuximab-based regimen used to treat metastatic colorectal cancer (mCRC) could be influenced by VEGFA polymorphisms. Materials & methods: We studied the effects of five polymorphisms in the VEGFA gene (-2549D/I, -1154G/A, -460T/C, +405G/C and +936C/T) on the outcome of 98 mCRC patients treated with FOLFIRI plus cetuximab. Results: Patients homozygous for the -2549D, -1154G and -460T alleles did exhibit higher response rates to treatment and longer progression-free survival compared with others. In addition, the DGTGC and IGCGC haplotypes were significantly associated with a lower risk of disease progression. Conclusion: These findings suggest that VEGFA genetic variations might influence response/resistance of FOLFIRI plus cetuximab treatment in mCRC patients.

Published
2015

11. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study

Author

Gilles Calais, Jean-Claude Ollier, Laurence Collette, Vincent Klein, Etienne Bardet, Jean-François Bosset, Suzana Stojanovic-Rundic, Christoph Glanzmann, Alexander Beny, Jean-Luc Van Laethem, Pierre Clavere, Dominique Marchal, Jordi Giralt, Michel Bolla, René-Jean Bensadoun, Philippe Maingon, Patrice Cellier, Laurent Mineur, University of Zurich, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Service d'oncologie et de radiothérapie, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut Sainte Catherine, Institut Sainte Catherine [Avignon], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institute for Oncology and Radiology of Serbia, Service de Radiothérapie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de Lutte Contre le Cancer Nantes Atlantique 'René Gauducheau' (CLCC), Département de cancérologie et radiothérapie, CHU Grenoble, Hôpital Erasme (Bruxelles), Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges, Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs., Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Male, Time Factors, Colorectal cancer, medicine.medical_treatment, Leucovorin, Kaplan-Meier Estimate, 0302 clinical medicine, Risk Factors, Antineoplastic Combined Chemotherapy Protocols, Cumulative incidence, Israel, Digestive System Surgical Procedures, Middle Aged, 10044 Clinic for Radiation Oncology, Neoadjuvant Therapy, 3. Good health, Intention to Treat Analysis, Europe, Survival Rate, Treatment Outcome, Oncology, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Disease Progression, 030211 gastroenterology & hepatology, Female, 2730 Oncology, Fluorouracil, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, 610 Medicine & health, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Adenocarcinoma, Disease-Free Survival, 03 medical and health sciences, Folinic acid, Young Adult, medicine, Humans, Survival rate, Aged, Neoplasm Staging, Proportional Hazards Models, Chemotherapy, business.industry, Rectal Neoplasms, Chemoradiotherapy, Adjuvant, medicine.disease, Surgery, Radiation therapy, Concomitant, business, Chemoradiotherapy
Abstract

Summary Background EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy—irrespective of timing—significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. Methods We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m 2 per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m 2 per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. Findings 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8–13·1), 10-year overall survival was 49·4% (95% CI 44·6–54·1) for the preoperative radiotherapy group and 50·7% (45·9–55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83–1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0–56·4) for the adjuvant chemotherapy group and 48·4% (43·6–53·0) for the surveillance group (HR 0·91, 95% CI 0·77–1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5–48·8) for the preoperative radiotherapy group and 46·4% (41·7–50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79–1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2–51·6) for the adjuvant chemotherapy group and 43·7% (39·1–48·2) for the surveillance group (HR 0·91, 95% CI 0·77–1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1–27·6) with radiotherapy alone, 11·8% (7·8–15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1–18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7–15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). Interpretation Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. Funding EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comite du Doubs.

Published
2014

12. Unexpected toxicity of cetuximab combined with conventional chemoradiotherapy in patients with locally advanced anal cancer: results of the UNICANCER ACCORD 16 phase II trial†

Author

L. Miglianico, D. Azria, E. Paris, Patrick Ezra, C. Lemanski, Beata Juzyna, Katty Malekzadeh, Anne Delarochefordiere, Emmanuel Rio, J.P. Pignon, Eric Deutsch, Isabelle Martel-Lafay, T. Conroy, Yves Becouarn, David Malka, Antonin Levy, Institut Gustave Roussy (IGR), CRLCC Val d'Aurelle - Paul Lamarque, Institut Curie [Paris], Centre Léon Bérard [Lyon], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Centre Hospitalier Privé Saint-Grégoire, Institut Bergonié [Bordeaux], UNICANCER [Paris], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Curie, Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), and Institut Bergonié - CRLCC Bordeaux

Subjects
Male, MESH: Radiotherapy, Phases of clinical research, Gastroenterology, chemoradiotherapy, MESH: Anus Neoplasms, 0302 clinical medicine, MESH: Cetuximab, cetuximab, Medicine, MESH: Chemoradiotherapy, MESH: Aged, 0303 health sciences, education.field_of_study, MESH: Middle Aged, Cetuximab, Hematology, Middle Aged, phase II, Anus Neoplasms, targeted therapy, MESH: Drug-Related Side Effects and Adverse Reactions, 3. Good health, Oncology, Fluorouracil, 030220 oncology & carcinogenesis, Female, MESH: Neoplasm Recurrence, Local, medicine.drug, Adult, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, anal cancer, Population, Antibodies, Monoclonal, Humanized, Loading dose, Disease-Free Survival, 03 medical and health sciences, Internal medicine, Anal cancer, Humans, education, Adverse effect, 030304 developmental biology, Aged, MESH: Humans, Radiotherapy, business.industry, toxicity, MESH: Adult, medicine.disease, MESH: Male, Surgery, MESH: Cisplatin, MESH: Antibodies, Monoclonal, Humanized, MESH: Disease-Free Survival, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cisplatin, Neoplasm Recurrence, Local, business, MESH: Fluorouracil, MESH: Female, Chemoradiotherapy
Abstract

Background The ACCORD 16 phase II trial aimed to evaluate the objective response rate after combination of conventional chemoradiotherapy (CRT) and cetuximab in locally advanced anal canal carcinoma (LAACC). Patients and methods Immunocompetent patients with histologically confirmed LAACC received CRT [45 gray (Gy)] in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), in combination with weekly dose of cetuximab (250 mg/m2 with a loading dose of 400 mg/m2 1 week before irradiation), and a standard dose boost (20 Gy). The trial was originally designed to include 81 patients to detect a 15% of objective response increase with the new combination in comparison with CRT. Results The trial was prematurely stopped after the declaration of 15 serious adverse events (SAEs) in 14 out of 16 patients. Five patients received the entire planned treatment, and the compliance was higher after amendments of the protocol. Among the 15 SAEs, 6 were unexpected. Grade (G) 3/4 acute toxic effects, observed in 88% patients, were general (n = 13, 81%), digestive (n = 9, 56%), dermatological (n = 5, 31%), infectious (n = 4, 25%), haematological (n = 3, 19%), and others (n = 9); and three patients suffered from six G3/4 late toxic effects. No treatment-related death was reported. All 11 assessable patients had an objective response consisting of six complete (55%) and five partial (45%) response 2 months after the end of the treatment. Thirteen patients were followed up with a median of 22 months [95% confidence interval (CI ): 18–27] and had a 1-year colostomy-free survival, progression-free and overall survival rate of 67% (95% CI: 40%–86%), 62% (95% CI: 36%–82%), and 92% (95% CI: 67%–99%), respectively. Conclusion CRT plus cetuximab was unacceptably toxic in this population of patients. Results of others phase II trials evaluating this combination are awaited to confirm these findings. Eudra CT No 2007-007029-38.

Published
2013

13. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for first relapse of ovarian cancer

Author

Classe, J. -M, Glehen, O., Decullier, E., Marc Bereder, J., Msika, S., Lorimier, G., Abboud, K., Meeus, P., Ferron, G., Quenet, F., Marchal, F., Gouy, S., Pomel, C., Pocard, M., Frederic Guyon, Bakrin, N., Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), CRLCC Paul Papin-CRLCC René Gauducheau, Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Nice (CHU Nice), Hopital Louis Mourier - AP-HP [Colombes], Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Hôpital Nord (Saint Etienne), Centre Léon Bérard [Lyon], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Institut Gustave Roussy (IGR), Centre Jean Perrin, CRLCC Jean Perrin, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Institut Bergonié - CRLCC Bordeaux, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and Institut Bergonié [Bordeaux]

Subjects
Adult, Ovarian Neoplasms, secondary surgery, Ovarian cancer relapse, Cytoreduction Surgical Procedures, Hyperthermia, Induced, Middle Aged, Combined Modality Therapy, Disease-Free Survival, Young Adult, Recurrence, hyperthermic intra-peritoneal chemotherapy, Humans, Female, Morbidity, Neoplasm Recurrence, Local, Injections, Intraperitoneal, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Aged
Abstract

International audience; BACKGROUND:To assess impact of surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients treated for a first relapse of ovarian cancer (FROC).PATIENTS AND METHODS:Patients with a FROC treated with second-line chemotherapy, surgery and HIPEC were retrospectively included from 13 Institutions. Studied parameters were interval free between the end of initial treatment and the first relapse, second-line chemotherapy, peritoneal cancer index and completeness of surgery, HIPEC, mortality and morbidity, pathological results and survival.RESULTS:From 2001 to 2010, 314 patients were included. The main strategy was secondary chemotherapy followed by surgery and HIPEC (269/314-85.6%). Mortality and morbidity rates were respectively 1% and 30.9%. Median follow-up was 50 months, 5-year overall survival was 38.0%, with no difference between platinum-sensitive or -resistant patients and 5-year disease-free survival was 14%.CONCLUSION:HIPEC allows encouraging survival in the treatment of FROC, better in case of complete surgery, with acceptable mortality and morbidity rates.

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