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1. Assessing Long-term Treatment Benefits Using Complementary Statistical Approaches: An In Silico Analysis of the Phase III Keynote-045 and Checkmate-214 Immune Checkpoint Inhibitor Trials

Author: Ana Cavillon, Damien Pouessel, Nadine Houédé, Fanny Mathevet, Jean Yves Dauxois, Christine Chevreau, Stéphane Culine, Jean-Pierre Delord, Raphael Porcher, Thomas Filleron, Institut Claudius Regaud, Département d'oncologie médicale, Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Institut de Mathématiques de Toulouse UMR5219 (IMT), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Equipe 5 : METHODS - Méthodes de l’évaluation thérapeutique des maladies chroniques (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'épidémiologie Clinique [Hôtel-Dieu], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Hôtel Dieu
Subjects: [STAT]Statistics [stat], Long-term benefit, Flexible parametric survival model with cure, Urology, [SDV]Life Sciences [q-bio], Milestone survival, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Immune checkpoint inhibitor, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology
Abstract: International audience; BackgroundThe Keynote-045 trial illustrates that the long-term benefit (LTB) of treatment does not always translate to improved progression-free survival (PFS). Milestone survival and flexible parametric survival model with cure (FPCM) have been proposed as complementary statistical approaches to more comprehensively evaluate LTBs of treatments.ObjectiveThe current study compares milestone survival and FPCM analyses to evaluate treatment effects of immune checkpoint inhibitor (ICI) phase III trials.Design, setting, and participantsIndividual patient data, from initial and follow-up analyses of Keynote-045 (urothelial cancer) and Checkmate-214 (advanced renal cell carcinoma), were reconstructed for PFS.Outcome measurements and statistical analysisEach trial was reanalyzed using the Cox proportional hazard regression and two complementary methods (milestone survival and FPCM) to estimate treatment impact on the LTB.Results and limitationsFor each trial, there was evidence of nonproportional hazards. For the long-term analysis of the Keynote-045 trial, FPCM identified a time-dependent effect on PFS, but the Cox model found no statistical difference in PFS (hazard ratio, 0.90; 95% confidence interval, 0.75–1.08). Milestone survival and FPCM identified improvements in the LTB fractions. This was consistent with the results from the reanalysis of Keynote-045, based on the shorter follow-up, although the LTB fraction was not retained. The increase in PFS in Checkmate-214 was identified by both Cox model and FPCM. Experimental treatment-dependent improvement in the LTB fraction was demonstrated using milestone survival and FPCM. The LTB fraction estimated with FPCM was consistent with the results from the reanalysis of the shorter follow-up period.ConclusionsAlthough ICIs show substantial shifts toward LTBs in terms of PFS, based on a conventional Kaplan-Meier or Cox model analysis, our approach provides an alternative assessment of benefit-risk ratios for new therapeutics and facilitates communicating risk to patients. Kidney patients treated with ICIs can be counseled that they are potentially cured, but future work will need to definitively validate this conclusion.
Published: 2023
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2. Cancer de la vessie localement avancé ou métastatique : identification des freins et leviers du parcours des patients en France

Author: Nadine, Houédé, Cécile, Flahault, Marine, Gross-Goupil, Solenn, Le Clanche, Yann, Le Goff, Frédérick, Merlier, Géraldine, Pignot, Bertrand, Pourroy, Constance, Thibault, Evanguelos, Xylinas, Marie-Noelle, Solbes, Gwenael, Dénéchère, Morgan, Roupret, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Laboratoire de Psychopathologie et Processus de Santé (LPPS (URP_4057)), Université Paris Cité (UPCité), CHU Bordeaux [Bordeaux], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service Pharmacie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pfizer Oncology, CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Initiatives, MESH: Humans, Prise en charge, Health Personnel, Accompagnement psychologique, Cancer de la vessie localement avancé, Family caregivers, MESH: Quality of Life, Locally advanced bladder cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Caregivers, Cancer de la vessie métastatique, Metastatic bladder cancer, MESH: Urinary Bladder Neoplasms, MESH: France, Caregivers, Urinary Bladder Neoplasms, Quality of Life, Parcours de soins, Humans, MESH: Health Personnel, France, Aidants, Psychological support, Healthcare pathway
Abstract: International audience; Introduction: Bladder cancer is currently ranked as the 8th most common cancer in France. However, the patient care pathway for this cancer is still not well known.Methods: A telephone survey was conducted with fifteen healthcare professionals, ten patients, and five family caregivers between November 2020 and March 2021. The objectives of this survey were to identify the major steps in the care pathway according to the medical, emotional and societal dimensions, for patients with locally advanced or metastatic bladder cancer, the associated barriers, and the initiatives to be implemented to improve it.Results: Several barriers were identified at different stages of the overall care pathway, including lack of knowledge of risk factors and warning signs of the disease by the general population and some healthcare professionals, difficulties linked to the announcement consultation, lack of psychological support for patients and their caregivers, and lack of information given about the disease and supportive care.Discussion: These results allowed us to identify three major initiatives which could improve the overall care pathway and the quality of life of patients and their caregivers: 1/implementation of a public awareness campaign on bladder cancer; 2/creation of booklets for patients and their caregivers to provide them with a source of reliable information; and 3/the creation of communication tools between healthcare professionals and patients to facilitate exchanges during consultations.; Introduction > Le cancer de la vessie est aujourd'hui classé en huitième position des cancers lesplus fréquents en France. Le parcours de soins de ce cancer est, cependant, mal connu.Méthodes > Une enquête téléphonique a été menée en France auprès de quinze professionnels desanté, dix patients et cinq aidants entre novembre 2020 et mars 2021. Les objectifs de cetteenquête étaient d'identifier les grandes étapes du parcours de soins des patients atteints d'uncancer de la vessie localement avancé ou métastatique, selon l'angle médical, émotionnel etsociétal, les freins y étant associés et les initiatives à mettre en place pour l'améliorer. IntroductionLe cancer d'origine vésicale est dans 90 % des cas un carcinomeurothélial, dont l'incidence est de 13 000 nouveaux cas diag-nostiqués chaque année en France [1], le plaçant en huitièmeposition des cancers les plus fréquents. Il arrive au quatrièmerang des cancers masculins et au quatorzième rang des cancersféminins et est responsable d'environ 5000 décès par an enFrance (3778 décès chez les hommes et 1235 décès chez lesfemmes, observés en 2017). Il est ainsi le septième cancer leplus mortel en France [1].Les principaux facteurs de risque du cancer de la vessie sontl'âge, avec une moyenne d'âge au diagnostic de 73 ans chezl'homme et 78 ans chez la femme [2], et le tabagisme [3]. Unfumeur a, en effet, environ 5,5 fois plus de risque de développerla maladie par rapport à un non-fumeur. En France, le tabagismeserait responsable de 53 % des cas de tumeurs de la vessie chezles hommes et de 39 % chez les femmes [4]. Les autres facteursde risque sont l'exposition professionnelle à des substances,comme les amines aromatiques, à des agents infectieux (ex :schistosome), ou à certains médicaments (ex : traitement anté-rieur à base de cyclophosphamide). Les facteurs de risqueassociés au carcinome urothélial en font historiquement uncancer principalement masculin [5].Le diagnostic de ce cancer peut être retardé, à cause de symp-tômes cliniques non spécifiques pouvant laisser penser, notam-ment, à une infection urinaire, tels qu'une augmentation de lafréquence urinaire, de l'urgence mictionnelle et une dysurie, quiRésultats > Plusieurs freins ont été identifiés à différentes étapes du parcours, notamment lemanque de connaissance des facteurs de risque et signes d'alerte de la maladie par le grand publicet certains professionnels de santé, les difficultés liées à la consultation d'annonce, le manqued'accompagnement psychologique pour les patients et aidants, le manque d'informations don-nées sur la maladie et les soins de support.Discussion > Ces résultats ont permis d'identifier ainsi trois grandes initiatives qui permettraientd'améliorer le parcours de soins dans sa globalité et la qualité de vie des patients et de leursaidants : 1/mise en place d'une campagne de sensibilisation du grand public sur le cancer de lavessie ; 2/création de livrets à destination des patients et de leurs aidants pour leur fournir unesource d'informations fiables ; et 3/la création d'outils de communication entre soignants etpatients pour faciliter les échanges lors des consultations.
Published: 2022
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3. Preliminary tolerance analysis of adjuvant chemotherapy in older patients after resection of stage III colon cancer from the PRODIGE 34-FFCD randomized trial

Author: Aparicio, T., Bouché, O., Etienne, P. L., Barbier, E., Mineur, L., Desgrippes, R., Guerin-Meyer, V., Hocine, F., Martin, J., Le Brun-Ly, V., Cretin, J., Desramé, J., Rinaldi, Y., Cany, L., Falandry, C., Lefevre, L. B., Marous, M., Terrebonne, E., Mosser, L., Turpin, J., Turpin, A., Bauguion, L., Reichling, C., Eynde, M., Carola, E., Hiret, S., UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Service d'oncologie médicale, UCL - (SLuc) Service d'hépato-gastro-entérologie, CarMeN, laboratoire, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Privé des Côtes d'Armor (HPCA), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service Biostatistiques et Informatique Médicale (CHU de Dijon) (DIM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Fédération Francophone de Cancérologie Digestive (FFCD), Institut Sainte Catherine [Avignon], CH de Saint-Malo [Broussais], Service d'Oncologie Médicale [Angers], Centre Paul Papin, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre Hospitalier Simone Veil de Beauvais [Beauvais], Clinique François Chénieux, Hôpital Dupuytren [CHU Limoges], Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Hôpital privé Jean Mermoz [Lyon], Hôpital Européen [Fondation Ambroise Paré - Marseille], Clinique Francheville [Périgueux], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'oncogénétique [Centre georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, CHU de la Martinique [Fort de France], Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Jacques Puel - Bourran [Rodez] (HJPB), Clinique Sainte Isabelle [Abbeville, France], Service d'oncologie médicale (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), CH Colmar, Cliniques Universitaires Saint-Luc [Bruxelles], Groupe Hospitalier Public du Sud de l'Oise [Creil] (GHPSO), CRLCC René Gauducheau, and Département d'oncologie médicale [Saint Herblain]
Subjects: Geriatric evaluation, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Hepatology, Older, Gastroenterology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Adjuvant chemotherapy, Colon cancer
Abstract: International audience; BACKGROUND: Colon adenocarcinoma mainly occurs in older patients. Oxaliplatin-based adjuvant chemotherapy improved disease-free survival after stage III colon cancer resection, but this improvement was not demonstrated in older patients. METHODS: The purpose of ADAGE-PRODIGE 34, randomized open phase III trial is to compare in patients over 70 years oxaliplatin plus fluoropyrimidine with fluoropyrimidine alone in fit patients (Group 1) and fluoropyrimidine with observation in frail patients (Group 2) after resection of stage III colon adenocarcinoma. We report a preliminary tolerance analysis on 50% of the first patients enrolled. RESULTS: The analysis was conducted on 491 patients (378 in Group 1 and 113 in Group 2). Patients in Group 2 were older and showed more frailty criteria than those in Group 1. Cumulative grade 3-5 toxicities were more frequent in patients treated with oxaliplatin in Group 1 or with fluoropyrimidine in Group 2 than in patients treated with fluoropyrimidine in Group 1. At least one course was deferred in more than half of the patients in all groups. Early treatment cessation was more frequent in Group 2. CONCLUSION: No safety concerns were raised for the continuation of accrual. The frailty criteria distribution suggests that the investigator's evaluation for group allocation was accurate.
Published: 2022
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4. Nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial

Author: Yann-Alexandre Vano, Réza Elaidi, Mostefa Bennamoun, Christine Chevreau, Delphine Borchiellini, Diane Pannier, Denis Maillet, Marine Gross-Goupil, Christophe Tournigand, Brigitte Laguerre, Philippe Barthélémy, Elodie Coquan, Gwenaëlle Gravis, Nadine Houede, Mathilde Cancel, Olivier Huillard, Philippe Beuzeboc, Laure Fournier, Arnaud Méjean, Xavier Cathelineau, Nicolas Doumerc, Philippe Paparel, Jean-Christophe Bernhard, Alexandre de la Taille, Karim Bensalah, Thibault Tricard, Thibaut Waeckel, Géraldine Pignot, Elena Braychenko, Stefano Caruso, Cheng-Ming Sun, Virginie Verkarre, Guillaume Lacroix, Marco Moreira, Maxime Meylan, Antoine Bougouïn, Letuan Phan, Christelle Thibault-Carpentier, Jessica Zucman-Rossi, Wolf Herman Fridman, Catherine Sautès-Fridman, Stéphane Oudard, Cancer Research and Personalized Medicine - CARPEM [Paris], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Association pour la Recherche de Thérapeutiques Innovantes en Cancérologie [Paris] (ARTIC), Institut Mutualiste de Montsouris (IMM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hôpital Saint-André, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Eugène Marquis (CRLCC), Institut de Cancérologie de Strasbourg Europe (ICANS), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Clinique d'Oncologie et de Radiothérapie [Tours] (CORAD), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Hôpital Foch [Suresnes], Service des Explorations Fonctionnelles Physiologiques [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hospices Civils de Lyon (HCL), Nouvel Hôpital Civil de Strasbourg, Service de Néphrologie-Dialyse-Transplantation rénale [CHU Caen], 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 de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: MESH: Humans, MESH: Carcinoma, Renal Cell / drug therapy, MESH: Angiogenesis Inhibitors / adverse effects, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Neoplasm Staging, MESH: Male, MESH: Prospective Studies, MESH: Ipilimumab, MESH: Lipase, Oncology, MESH: Tumor Microenvironment, MESH: Sunitinib, MESH: Biomarkers, MESH: Antineoplastic Combined Chemotherapy Protocols / adverse effects, MESH: Female, MESH: Nivolumab / adverse effects, MESH: Protein Kinase Inhibitors / adverse effects
Abstract: International audience; Background: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.Methods: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment.Findings: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.Interpretation: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.
Published: 2022
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5. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial

Author: Greillier, Laurent, Monville, Florence, Leca, Vanina, Vely, Frédéric, Garcia, Stephane, Ciccolini, Joseph, Sabatier, Florence, Ferrani, Gilbert, Boudai, Nawel, Ghezali, Lamia, Landri, Marcellin, Marin, Clémence, Hamimed, Mourad, Arnaud, Laurent, Karlsen, Melanie, Atsou, Kevin, Bokobza, Sivan, Fleury, Pauline, Boyer, Arnaud, Audigier-Valette, Clarisse, Martinez, Stéphanie, Pegliasco, Hervé, Ray, Patrice, Falchero, Lionel, Serre, Antoine, Cloarec, Nicolas, Lebas, Louisiane, Hominal, Stephane, Barre, Patricia, Zahi, Sarah, Frikha, Ahmed, Bory, Pierre, Ray, Maryannick Le, Laborde, Lilian, Martin, Virginie, Malkoun, Richard, Roumieux, Marie, Mazieres, Julien, Perol, Maurice, Vivier, Eric, Benzekry, Sébastien, Fieschi, Jacques, Barlesi, Fabrice, Service d'oncologie multidisciplinaire innovations thérapeutiques [Hôpital Nord - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Veracyte SAS, Aix Marseille Université (AMU), Assistance Publique - Hôpitaux de Marseille (APHM), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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), Innate Pharma, Hôpital Saint-Joseph [Marseille], Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, Centre Hospitalier d'Aix en Provence [Aix-en-Provence] (CHIAP ), Hôpital Européen [Fondation Ambroise Paré - Marseille], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Nord-Ouest de Villefranche-sur-Saône, Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Centre Hospitalier Henri Duffaut (Avignon), Centre Hospitalier du Val d'Ariège, Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre hospitalier Jean Rougier, Centre hospitalier de Montauban (CH Montauban), Polyclinique Maymard, Centre Hospitalier de Bastia, Partenaires INRAE, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpitaux de Toulouse, Centre Léon Bérard [Lyon], Institut Gustave Roussy (IGR), and Université Paris-Saclay
Subjects: [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy
Abstract: International audience; Abstract Background: Resistance to PD1/L1 immune checkpoint inhibitors (ICIs) in advanced NSCLC patients is observed in about 80% of individuals with no robust predictive biomarker yet. The PIONeeR trial (NCT03493581) aims to predict such resistances through a comprehensive multiparametric biomarkers analysis. Methodology: Among the >300 advanced NSCLC patients (pts) recruited in PIONeeR, we focused on the first 137 ≥2nd line ECOG PS0-1 pts treated with single-agent nivolumab, pembrolizumab or atezolizumab. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout the 24 weeks post C1D1. Response to PD1/L1 ICIs was assessed by RECIST 1.1 every 6 weeks. Immune contexture was characterized in tumor & blood of each pt through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC/digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma dosage, leading to 331 measured biomarkers in addition to routine clinical parameters. Multivariable (MV) logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histological type & PDL1+ Tumor Cells) with the risk of Early Progression (EP), i.e. within 3.5 months of treatment. Multivariable Cox regression analysis was conducted for association with PFS and OS. Results: Overall, the 137 pts were mainly male (64%), smokers (92%) and 1% PDL1+ TC in 36% of the cases, and 21% of pts were still on treatment at data cut-off. Archived samples were available for 80% of pts at inclusion and re-biopsy was available in 52.9% of these cases. The median follow up was 19.8 months, 22.5% of pts did not progress at data cut-off while 62% presented EP. Tumor Cytotoxic T-cells density, especially PD1+ were lower in EP (MV OR=0.45, p=0.022); conversely, higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in EP (MV OR=3.8, p65% inter-pt variability was observed in plasma exposures for all ICIs, with 8-10% of pts displaying trough levels below the target engagement threshold. Data will be presented through unsupervised clustering algorithms & multi-modal supervised learning methods. Changes after 6 weeks of treatment will be analyzed to further investigate drugs mechanisms of action. Conclusion: The PIONeeR trial provides with the 1st comprehensive biomarkers’ analysis to establish predictive models of resistance in advanced NSCLC pts treated with PD1/L1 ICIs and highlights how tumor and circulating biomarkers are complementary.
Published: 2022
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6. Cabozantinib-nivolumab sequence in metastatic renal cell carcinoma: The CABIR study

Author: Yann‐Alexandre Vano, Letuan Phan, Gwenaelle Gravis, Iphigénie Korakis, Friederike Schlürmann, Denis Maillet, Mostefa Bennamoun, Nadine Houede, Delphine Topart, Delphine Borchiellini, Philippe Barthelemy, Raffaele Ratta, Thomas Ryckewaert, Ali Hasbini, Sophie Hans, Sheik Emambux, Sandra Cournier, Elena Braychenko, Réza‐Thierry Elaidi, Stéphane Oudard, Cancer Research and Personalized Medicine - CARPEM [Paris], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut Mutualiste de Montsouris (IMM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), ChemBioPharm, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Département de Radio-Oncologie [Brest] (Clinique Pasteur), Clinique Pasteur [Brest], Département de radiologie, Institut Gustave Roussy (IGR), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [Montsouris], Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), 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), Pôle de Chirurgie Oncologique générale, Gynécologique et Mammaire [Centre Antoine-Lacassagne], UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Institut de Cancérologie de Strasbourg Europe (ICANS), Hôpital Foch [Suresnes], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and PSEN Pharm
Subjects: Cancer Research, Pyridines, [SDV]Life Sciences [q-bio], Tyrosine kinase inhibitor, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Anilides, Humans, MESH: Protein Kinase Inhibitors, Anilides, Carcinoma, Renal Cell, Protein Kinase Inhibitors, Retrospective Studies, MESH: Humans, MESH: Pyridines, Cabozantinib, MESH: Retrospective Studies, MESH: Carcinoma, Renal Cell, Kidney Neoplasms, Renal cell carcinoma, Nivolumab, Oncology, Matching-adjusted study, MESH: Antineoplastic Agents, MESH: Nivolumab, Immunotherapy, MESH: Kidney Neoplasms
Abstract: International audience; Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS2-3 ). Key secondary endpoints included overall survival from second line (OS2 ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS2-3 and OS2 , NC sequence was superior to CN (PFS2-3 : HR = 0.58 [0.34-0.98], P = .043; OS2 : 0.66 [0.42-1.05], P = .080). Superior PFS2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFSL3 with cabozantinib when given after nivolumab (P
Published: 2022
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7. A Phase II Multicenter Trial on High-Dose Vitamin D Supplementation for the Correction of Vitamin D Insufficiency in Patients with Breast Cancer Receiving Adjuvant Chemotherapy

Author: Elodie Chartron, Nelly Firmin, Célia Touraine, Angélique Chapelle, Eric Legouffe, Lobna Rifai, Stéphane Pouderoux, Lise Roca, Véronique D’Hondt, William Jacot, Département d'oncologie Médicale, CRLCC Val d'Aurelle - Paul Lamarque, Institut du Cancer de Montpellier (ICM), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), ONCOGARD - NIMES, Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), 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), and UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM)
Subjects: Adult, Nutrition and Dietetics, Nutrition. Foods and food supply, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Middle Aged, Vitamin D Deficiency, Article, adjuvant chemotherapy, Treatment Outcome, breast cancer, Chemotherapy, Adjuvant, Dietary Supplements, Humans, TX341-641, Female, Vitamin D, vitamin D insufficiency, Biomarkers, Food Science, hypercalciuria, Aged
Abstract: International audience; Breast cancer (BC) treatments induce vitamin D (VD) insufficiency and bone metabolism changes, resulting in osteoporosis and skeletal morbidity risk. We report the results of a bicentric phase II trial (ClinicalTrials.gov Identifier: NCT04091178) on the safety and efficacy of high-dose oral VD supplementation for VD deficiency correction in 44 patients with early BC treated with adjuvant chemotherapies. Patients received one dose of 100,000 IU 25-OH VD every 3 weeks from day 1 of cycle 1 to day 1 of cycle 5. The primary endpoint was the percentage of patients achieving serum 25-OH VD concentration normalization on day 1 of cycle 6 (D1C6). Secondary endpoints were safety, VD and calcium parameters at baseline and during chemotherapy, and identification of predictive biomarkers of VD normalization on D1C6. On D1C6, 21 patients (47.7%, 95% CI: 33.0–62.8) achieved VD normalization. No VD-related clinical toxicity was reported. However, 13 patients (29.5%) presented asymptomatic grade 1 hypercalciuria, leading to interruption of the high-dose oral VD supplementation in 10, followed by a rapid reduction in serum VD concentration. No baseline clinical factor was predictive of VD normalization on D1C6. This high-dose VD supplementation appears safe and efficient in patients with early BC receiving adjuvant chemotherapy.
Published: 2021
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8. PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

Author: Hanane Agherbi, Fanny Leenhardt, Litaty Mbatchi, Aurélie Garcin, Philippe Pourquier, Alexandre Evrard, Candice Marchive, Alice Matheux, Matthieu Gassiot, Nadine Houede, Abdelhay Boulahtouf, Gaëlle Fromont, Patrick Balaguer, Eve Combes, Céline Gongora, Eric Fabbrizio, 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), Gongora, Céline, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut du Cancer de Montpellier (ICM), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD)
Subjects: 0301 basic medicine, Cancer Research, Afatinib, PXR, [SDV]Life Sciences [q-bio], afatinib, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, digestive system, Article, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Prostate, medicine, kinase inhibitors, RC254-282, Pregnane X receptor, Chemistry, Kinase, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, biomarkers, Dabrafenib, medicine.disease, prostate cancer, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, digestive system diseases, 3. Good health, Dasatinib, 030104 developmental biology, medicine.anatomical_structure, Oncology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer research, SLC16A1, Erlotinib, Biomakers, medicine.drug
Abstract: Simple Summary Many kinase inhibitors have been tested as potential alternatives for the treatment of castration-resistant prostate cancers. However, none of these clinical trials led to drug approval despite interesting responses. Our study reveals that genes involved in drug metabolism and their master regulator PXR (Pregnane X Receptor) could be responsible, at least in part, for these disappointing results as they can modulate tumor cell response to specific kinase inhibitors. We found that stable expression of PXR sensitized prostate cancer cells to erlotinib, dabrafenib, and afatinib, while it rendered cells resistant to dasatinib and had no effect for other inhibitors tested. We also report for the first time that sensitization to afatinib is due to an alteration in drug transport that involves the SLC16A1 monocarboxylate transporter. Together, our results further indicate that PXR might be considered as a biomarker of response to kinase inhibitors in castration-resistant prostate cancers. Abstract Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.
Published: 2021
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9. Clinical and biological characteristics of leukemia cutis in chronic lymphocytic leukemia: A study of the French innovative leukemia organization (FILO)

Author: Anne Lavaud, Audrey Bidet, Damien Roos-Weil, Benjamin Carpentier, Stéphane Leprêtre, Antoine Martin, Lauren Veronese, Alain Delmer, Loic Ysebaert, Bénédicte Hivert, Julien Broséus, Anne Corby, Eric Van Den Neste, Stéphanie Poulain, Agathe Waultier Rascalou, Kamel Laribi, Damien Luque Paz, Romain Guieze, Lise Willems, Jérôme Paillassa, Fatiha Merabet, Jean-Philippe Vial, Fanny Baran-Marszak, Pierre Feugier, Albane Ledoux-Pilon, Anne Quinquenel, Michaël Munger, Florence Cymbalista, Virginie Eclache, Eve Maubec, Chloé Friedrich, Marie-Sarah Dilhuydy, Lysiane Molina, Grégory Lazarian, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre du cancer, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Hôpital de l'Enfant-Jésus [CHU Québec] (HEJ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), CRHU Nancy, Unité clinique de pathologie neuromusculaire [CHU Pitié-Salpêtrière], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Le Mans (CH Le Mans), Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cliniques Universitaires Saint-Luc [Bruxelles], Centre Hospitalier de la Rochelle (CH la Rochelle), Centre de Biologie Pathologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Avicenne [AP-HP], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), FAYE, Fatimata, Signalisation, Microenvironnement et Hémopathies Lymphoïdes B (SIMHEL), Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord-Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Oncology, Adult, Male, medicine.medical_specialty, Skin Neoplasms, Chronic lymphocytic leukemia, Internal medicine, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Aged, Skin, Aged, 80 and over, B-Lymphocytes, business.industry, Leukemia cutis, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Leukemia, Treatment Outcome, Mutation, Female, France, medicine.symptom, business
Abstract: TO THE EDITOR : Patients with chronic lymphocytic leukemia (CLL) exhibit a variety of skin lesions including mostly non-specific cutaneous manifestations (such as cutaneous infections or exaggerated reactions to insect bite) and secondary cutaneous malignancies, as patients are at high risk of developing basal cell carcinoma, squamous cell carcinoma, melanoma, and Merkel cell carcinoma. Specific cutaneous infiltration by neoplastic B lymphocytes with clinically identifiable skin lesions, also called leukemia cutis (LC), is more uncommon and has seldom been reported in chronic lymphocytic leukemia. [...]
Published: 2021
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10. Feasibility and efficacy of a supervised home-based physical exercise program for metastatic cancer patients receiving oral targeted therapy: study protocol for the phase II/III - UNICANCER SdS 01 QUALIOR trial

Author: Sophie Abadie-Lacourtoisie, Isabelle Durand-Zaleski, Jean-Marc Descotes, C. Lefeuvre-Plesse, Nadine Houede, Nathalie Menneveau, Amélie Anota, Claire Garnier-Tixidre, Carole Helissey, Laetitia Stefani, Soazig Nenan, Florence Joly, Isabelle Rieger, Alain Zannetti, Sébastien Salas, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre Eugène Marquis (CRLCC), Institut Daniel Hollard [Grenoble], HIA Bégin, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier de Cholet (CHC), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Département d'oncologie médicale [Saint Herblain] (Centre René Gauducheau - ICO), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, CH Annecy Genevois, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Diagnostic et de Thérapeutique, Hôpital de l’Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and CAMI Sport et Cancer
Subjects: Quality of life, Male, Cancer Research, medicine.medical_specialty, Colorectal cancer, Medico-economy, medicine.medical_treatment, Pain, Administration, Oral, Physical exercise, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Targeted therapy, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Breast cancer, Internal medicine, Genetics, medicine, Humans, 030212 general & internal medicine, Oral targeted therapy, Neoplasm Metastasis, Lung cancer, Fatigue, business.industry, Cancer, Adherence to treatment, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Supervised physical exercise programs, 3. Good health, Exercise Therapy, Oncology, 030220 oncology & carcinogenesis, Feasibility Studies, Psychological and cognitive functions, Female, business, Kidney cancer, Metastatic cancer, Supportive care
Abstract: Background Currently, oral targeted therapies are known to be effective and are frequently used to treat metastatic cancer patients, but fatigue is a frequently reported early side effect of these treatments. This fatigue may impact the patient’s treatment adherence and result in a negative impact on quality of life. Physical exercise significantly improved the general well-being and quality of life of advanced cancer patients. However, there is no specific physical activity program adapted for patients with advanced disease. Methods QUALIOR is a two-part, randomized, open-label, and multicenter with two arms phase II/III trial. Patients (phase II: n = 120; phase III: n = 312) with metastatic cancer (breast cancer, kidney cancer, lung cancer, and other cancers [including but not limited to colon cancer, melanoma, sarcoma, or hepatocarcinoma]) treated with a first- or second-line oral targeted therapy without chemotherapy will be included. Patients will be randomized (2:1) to a 3-month supervised home-based standardized physical activity program or to a recommended adapted physical activity (via a booklet). The primary objective of the phase II is to evaluate the feasibility of the supervised program. The primary objective of the phase III is the evaluation of the benefit of the supervised home-based program compare to the recommended program in terms of fatigue and quality of life at 3 months. The secondary objectives aim to evaluate the impact of the supervised program on fatigue over time, pain, physical capacities, psychosocial and cognitive functions, general quality of life, frequency of dose reduction and patients’ adherence to the targeted therapy, overall survival, and progression-free survival. This study will also evaluate the medico-economic impact of supervised program compared to the recommended adapted physical activity program. Discussion The aim of this study is to evaluate home-based physical exercise program for metastatic cancer patients treated with oral targeted therapies to help patients to cope with fatigue and improve quality of life. Trial registration This trial was registered in ClinicalTrials.gov since May 2017 (NCT03169075).
Published: 2020
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11. Impact of iterative reconstructions on image quality and detectability of focal liver lesions in low-energy monochromatic images

Author: Jean Paul Beregi, Djamel Dabli, Aymeric Hamard, J.M. Teissier, Joël Greffier, J. Frandon, Hugo Pasquier, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), General Electric Medical Systems [Buc] (GE Healthcare), and General Electric Medical Systems
Subjects: MESH: Radiation Dosage, Carcinoma, Hepatocellular, Image quality, Multidetector Computed tomography, Biophysics, General Physics and Astronomy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Iterative reconstruction, Radiation Dosage, Dose level, MESH: Carcinoma, Hepatocellular / diagnostic imaging, Imaging phantom, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Low energy, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Radiology, Nuclear Medicine and imaging, Image resolution, Physics, MESH: Humans, Phantoms, Imaging, business.industry, Liver Neoplasms, General Medicine, MESH: Liver / diagnostic imaging, MESH: Tomography, X-Ray Computed / methods, MESH: Liver Neoplasms / diagnostic imaging, MESH: Phantoms, Imaging, Liver, Dual-energy, 030220 oncology & carcinogenesis, Task-based image quality assessment, Radiographic Image Interpretation, Computer-Assisted, MESH: Radiographic Image Interpretation, Computer-Assisted / methods, Spatial frequency, Monochromatic color, Tomography, X-Ray Computed, Nuclear medicine, business
Abstract: International audience; Purpose: To assess the impact of iterative reconstructions on image quality and detectability of focal liver lesions in low-energy monochromatic images from a Fast kV-Switching Dual Energy CT (KVSCT) platform.Methods: Acquisitions on an image-quality phantom were performed using a KVSCT for three dose levels (CTDIvol:12.72/10.76/8.79 mGy). Raw data were reconstructed for five energy levels (40/50/60/70/80 keV) using Filtered Back Projection (FBP) and four levels of ASIR (ASIR30/ASIR50/ASIR70/ASIR100). Noise power spectrum (NPS) and task-based transfer function (TTF) were measured before computing a Detectability index (d') to model the detection task of liver metastasis (LM) and hepatocellular carcinoma (HCC) as function of keV.Results: From 40 to 70 keV, noise-magnitude was reduced on average by -68% ± 1% with FBP; -61% ± 3% with ASIR50 and -52% ± 6% with ASIR100. The mean spatial frequency of the NPS decreased when the energy level decreased and the iterative level increased. TTF values at 50% decreased as the energy level increased and as the percentage of ASIR increased. The detectability of both lesions increased with increasing dose level and percentage of ASIR. For the LM, d' peaked at 70 keV for all reconstruction types, except for ASIR70 at 12.72 mGy and ASIR100, where d' peaked at 50 keV. For HCC, d' peaked at 60 keV for FBP and ASIR30 but peaked at 50 keV for ASIR50, ASIR70 and ASIR100.Conclusions: Using percentage of ASIR above 50% at low-energy monochromatic images could limit the increase of noise-magnitude, benefit from spatial resolution improvement and hence enhance detectability of subtle low contrast focal liver lesions such as HCC.
Published: 2020
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12. PD-L1 expression and pattern of immune cells in pre-treatment specimens are associated with disease-free survival for HR-NMIBC undergoing BCG treatment

Author: Morgan Rouprêt, Evanguelos Xylinas, Leonor Chaltiel, Yann Neuzillet, Jeanne Piana-Thomassin, Serge Brunelle, Géraldine Pignot, Mathieu Roumiguié, Juliette Cotte, François Audenet, Eva Compérat, Gregory Verhoest, Nadine Houede, Stéphane Larré, Alexandra Masson-Lecomte, Pierre Colin, François Xavier Nouhaud, 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), Hôpital de Rangueil, CHU Toulouse [Toulouse], Groupe de Recherche Clinique Onco-Urologie Prédictive [CHU Tenon] (GRC 5), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Claudius Regaud, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), CHU Rouen, Normandie Université (NU), CHU Pontchaillou [Rennes], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ramsay Générale de Santé - Hôpital Privé La Louvière, 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), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Centre Hospitalier Universitaire de Reims (CHU Reims), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Foch [Suresnes], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Salvy-Córdoba, Nathalie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, Male, Nephrology, medicine.medical_specialty, T-Lymphocytes, Urology, medicine.medical_treatment, 030232 urology & nephrology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Risk Assessment, Gastroenterology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, B7-H1 Antigen, Disease-Free Survival, PD-L1/PD-1 checkpoint inhibitor, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Adjuvants, Immunologic, Internal medicine, Tumor Cells, Cultured, medicine, Humans, Neoplasm Invasiveness, BCG, Stage (cooking), Aged, Retrospective Studies, Aged, 80 and over, Bladder cancer, business.industry, Proportional hazards model, Carcinoma in situ, Immunotherapy, Middle Aged, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, Log-rank test, Administration, Intravesical, Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, Concomitant, BCG Vaccine, Female, business, Non-muscle invasive bladder cancer
Abstract: International audience; Purpose: To assess the association between PD-L1 expression and disease-free survival (DFS) in High-Risk Non-Muscle Invasive Bladder Cancer (HR-NMIBC) patients treated with intravesical Bacillus Calmette-Guerin (BCG) instillations (IBI).Methods: Retrospective study in five French centres between 2001 and 2015. Participants were 140 patients with histologically confirmed HR-NMIBC. All patients received induction and maintenance IBI. Pathological stage/grade, concomitant carcinoma in situ, lesion number and tumour size were recorded. CD3, CD8 and PD-L1 expression in tumour cells and in T cells in the tumour microenvironment (TME) was determined immunohistochemically. Median follow-up was 54.2 months. The primary outcome measure was DFS. Univariable and multivariable analyses were performed using the log rank test and Cox proportional hazards model.Results: Of the 140 NMIBC, 52 (37.1%) were Ta, 88 (62.9%) were T1 and 100% were high grade. Median number of maintenance IBI was six (range 1-30). Twenty-five (17.9%) patients had recurrence/progression. In multivariable analysis, age (HR 1.07 [95% CI 1.02-1.13], p = 0.009), PD-L1 expression in tumour cells (HR per 10 units = 1.96 [95% CI 1.28-3.00], p = 0.02) and CD3/CD8 ratio (HR per 10 units = 3.38 [95% CI 1.61-7.11], p = 0.01) were significantly associated with DFS. However, using the cut-off corresponding for each PD-L1 antibodies, PD-L1 + status was not associated with DFS.Conclusion: Despite an association between PD-L1 expression and BCG failure in HR-NMIBC, the PD-L1 + status was not a prognostic factor in the response of BCG. Moreover, we confirmed the key role played by the IC within the microenvironment in BCG treatment. These findings highlighted the rationale to combine BCG and PD-L1/PD-1 antibodies in early bladder cancer.
Published: 2020
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13. Traitement des oligometastases et oligoprogression

Author: I. Latorzeff, O. Riou, M.-P. Farcy-Jacquet, C. Lemanski, P. Boisselier, D. Azria, C. Llacer, Céline Bourgier, Pascal Fenoglietto, M. Charissoux, CCSD, Accord Elsevier, 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), Clinique Pasteur [Toulouse], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), and Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD)
Subjects: Gynecology, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], Oligométastases, 3. Good health, Stereotactic radiotherapy, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Radiothérapie stéréotaxique, medicine, Radiology, Nuclear Medicine and imaging, business, Oligometastases
Abstract: Resume Nous proposons dans cette revue de rapporter l’impact de la radiotherapie stereotaxique chez les patients ayant un cancer oligometastatique ou en oligoprogression en termes de survie sans progression metastatique et globale, et d’identifier quelle est la place de cette modalite de radiotherapie au sein du parcours–patient.
Published: 2019
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14. OC-0284: First results of the French cohort ANABASE : treatment and outcome in non-metastatic anal cancer

Author: C. Lemanski, David Tougeron, A. de la Rochefordière, M. Saliou, Véronique Vendrely, Eric Francois, Côme Lepage, O. Bouche, J. Cretin, N. Bonichon-Lamichhane, Emilie Barbier, P. Pommier, O. Diaz, Laurent Quero, P. Ronchin, N. Baba Hamed, CHU Bordeaux [Bordeaux], UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Service d'oncologie médicale (Centre Antoine Lacassagne, Nice), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-UNICANCER, Fédération Francophone de la Cancérologie Digestive, FFCD, Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinique Tivoli Ducos [Bordeaux], Institut Curie [Paris], Centre Hospitalier Universitaire de Reims (CHU Reims), Service d’hépato-gastro-entérologie et assistance nutritive [CHU de Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut Daniel Hollard [Grenoble], Centre Léon Bérard [Lyon], Centre Azureen de cancérologie, Clinique Mutualiste de l'Estuaire (Saint Nazaire), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), université de Bourgogne, LNC, UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Centre Antoine Lacassagne de Nice, Groupe hospitalier Paris Saint-Joseph - Hôpital, Clinique Tivoli-Ducos, Institut Curie, Institut de Cancérologie du GARD (Instit Cancéro - GARD), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Oncology, medicine.medical_specialty, business.industry, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, Hematology, 021001 nanoscience & nanotechnology, medicine.disease, Outcome (game theory), 3. Good health, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Internal medicine, Cohort, 0202 electrical engineering, electronic engineering, information engineering, medicine, Non metastatic, Anal cancer, 020201 artificial intelligence & image processing, Radiology, Nuclear Medicine and imaging, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 0210 nano-technology, business
Abstract: IF 4.942 (2017); International audience
Published: 2018

15. Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations

Author: Serge Carillo, Aurélie Chauveau, Stéphane Giraudier, Jean-Jacques Kiladjian, Emmanuelle Verger, Valérie Ugo, Mohammed A. Yassin, Bruno Cassinat, Christine Chomienne, Marie-Hélène Schlageter, Jean-Christophe Ianotto, Eric Legouffe, Nader Al-Dewik, Christine Dosquet, Unite de Biologie Cellulaire (Biol Cell - ST LOUIS - PARIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'hématologie (Labo Hémato - BREST), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité de Formation de Recherche de Médecine (UFRM - BREST), Université de Brest (UBO), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de cancérologie et d'hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Department of Hematology and Bone Marrow Transplant (DHBMT - DOHA - QATAR), National Center for Cancer Care and Research (NCCCR - DOHA - QATAR), Qatar Medical Genetic Center (QMGC - DOHA - QATAR), Hamad medical corporation, Département de Cytologie Clinique (Dep Cyto Clin - NIMES), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), ONCOGARD - NIMES, Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Université d'Angers - Faculté de médecine (UA UFR Médecine), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire d'Hématologie Biologique (Hémato - ANGERS), Centre Hospitalier Universitaire d'Angers (CHU Angers), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigations Cliniques, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Oncology, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Gene mutation, medicine.disease_cause, Biochemistry, Somatic evolution in cancer, Polyethylene Glycols, 0302 clinical medicine, Hydroxyurea, interferon-a therapy, 0303 health sciences, Mutation, essential thrombocythemia, biology, Remission Induction, Hematology, Middle Aged, Isocitrate Dehydrogenase, Recombinant Proteins, 3. Good health, DNA-Binding Proteins, 030220 oncology & carcinogenesis, Female, Thrombocythemia, Essential, CALR mutations, Adult, medicine.medical_specialty, Adolescent, Immunology, Alpha interferon, IDH2, Dioxygenases, Clonal Evolution, Young Adult, 03 medical and health sciences, Proto-Oncogene Proteins, Internal medicine, medicine, Humans, Allele, Alleles, 030304 developmental biology, Aspirin, Essential thrombocythemia, Interferon-alpha, Off-Label Use, Cell Biology, Genes, p53, medicine.disease, Clone Cells, Repressor Proteins, biology.protein, Calreticulin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: International audience; Myeloproliferative neoplasms are clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis. Few therapeutic options are available, among which interferon α (IFNα) presents interesting properties like the ability to induce hematologic responses (HRs) and molecular responses (MRs) in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). HR was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and 2 patients even achieved complete MR. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next-generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2, and TP53 genes). The presence of additional mutations was associated with poorer MR on CALR mutant clones, with only minor or no MRs in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient, but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of HRs and MRs in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy.
Published: 2015
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16. 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
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17. Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18 F-Misonidazole PET/CT in Patients with Non–Small Cell Lung Carcinoma (RTEP5 Study)

Author: Romain Modzelewski, Mathieu Salaün, Fabrice Denis, Naji Salem, Pierre Bohn, Jean-Pierre Muratet, Pierre Olivier, Sophie Guillemard, Nicolas Aide, Enrique Chajon, Laurent Vervueren, Pierre Vera, Alina Berriolo Riedinger, Claire Houzard, Marie Lacombe, Françoise Mornex, Etienne Martin, Maximilien Vermandel, Nathalie Charrier, P.O. Kotzki, Frédéric Courbon, Anne Devillers, Véronique Beckendorf, S. Danhier, Carole Massabeau, Marc-André Mahé, Eric Dansin, P. Boisselier, Philippe Chaumet-Riffaud, Philippe Fernandez, Sébastien Thureau, Amaury Paumier, Marie-Pierre Farcy Jacquet, Hélène Kolesnikov-Gauthier, Amandine Pallardy, Sébastien Hapdey, Bernard Dubray, Service de médecine nucléaire [Rouen], CRLCC Haute Normandie-CRLCC Henri Becquerel, Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service de Biophysique et de Médecine Nucléaire, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Therapies Interventionnelles Assistees Par l'Image et la Simulation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Service de Médecine Nucléaire [Nantes], Hôpital Laennec, CRLCC René Gauducheau, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, 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), Service de médecine nucléaire [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Lab-STICC_UBO_CACS_MOCS, Université de Brest (UBO)-Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Centre Alexis Vautrin (CAV), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CRLCC Eugène Marquis (CRLCC), Département de médecine nucléaire [Rennes], 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), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire [CHU Caen], 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), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Centre Jean Bernard (ILC Le Mans), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), UNICANCER-Université Lille Nord de France (COMUE), 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), Centre de Recherches en Cancérologie de Toulouse (CRCT), Centre National de la Recherche Scientifique (CNRS)-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), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CRLCC Paul Papin, Centre des Sciences de la Terre, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de pneumologie, oncologie thoracique et soins intensifs respiratoires [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Département de radiothérapie et de physique médicale, CRLCC Henri Becquerel, Département de Radiothérapie, Centre René Gauducheau-Institut de Cancérologie de l'Ouest (ICO)-Centre de Lutte Contre le Cancer Nantes Atlantique 'René Gauducheau' (CLCC), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), CRLCC Paul Papin-CRLCC René Gauducheau, CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), 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), Département de Radiation oncologie, CGFL, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), and Department of Radiation Oncology, Centre Hospitalier Universitaire Lyon Sud, Pierre Benite, France
Subjects: Misonidazole, positron emission tomography, medicine.medical_treatment, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Carcinoma, medicine, Radiology, Nuclear Medicine and imaging, fluoro-deoxy-D-glucose, Lung cancer, Survival rate, Radiation oncologist, Pneumonitis, f-misonidasole, business.industry, hypoxia, medicine.disease, 3. Good health, radiotherapy dose, Radiation therapy, lung cancer, chemistry, 030220 oncology & carcinogenesis, business, Nuclear medicine
Abstract: International audience; See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant (18)F-misonidazole ((18)F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The (18)F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In (18)F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-β = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were (18)F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the (18)F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the (18)F-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the (18)F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. (18)F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.
Published: 2017
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18. Feasibility of Fibered Monitoring System for Pulsed Dose-Rate Facilities Based on Radioluminescence of SrS:Ce,Sm Phosphor

Author: Jean-Roch Vaillé, B. Brichard, D. Benoit, P. Garcia, S. Matias-Vaille, J. Lautissier, J. Isturiz, Laurent Dusseau, Methods and engineering of multiscale computing from atom to continuum ( MICMAC ), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -École des Ponts ParisTech ( ENPC ), Institut d’Electronique et des Systèmes ( IES ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Electronique, Informatique et Image ( Le2i ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, ONCOGARD - NIMES, Institut de Cancérologie du GARD ( Instit Cancéro - GARD ), Centre d'oncologie et de radiothérapie du parc [Dijon], Centre d'Etude de l'Energie Nucléaire ( SCK-CEN ), Centre Spatial Universitaire de Montpellier-Nîmes ( CSU ), Université de Montpellier ( UM ), Institut d’Electronique et des Systèmes (IES), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Radiations et composants (RADIAC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD), Centre d'Etude de l'Energie Nucléaire (SCK-CEN), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Arts et Métiers (ENSAM), and HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: Nuclear and High Energy Physics, medicine.medical_specialty, Photoluminescence, Photon, Materials science, Optical fiber, Phosphor, Signal, 030218 nuclear medicine & medical imaging, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, medicine, Dosimetry, Medical physics, Electrical and Electronic Engineering, ComputingMilieux_MISCELLANEOUS, business.industry, Radioluminescence, [SPI.TRON]Engineering Sciences [physics]/Electronics, [ SPI.TRON ] Engineering Sciences [physics]/Electronics, Nuclear Energy and Engineering, 030220 oncology & carcinogenesis, Optoelectronics, business, Luminescence
Abstract: International audience; The possibility to monitor pulsed dose-rate facilities by means of real-time fibered dosimetry is investigated. A system based on the luminescence of the SrS:Ce,Sm is used to monitor pulses from a medical accelerator with four different dose-rates. The RL signal is characterized using a dedicated acquisition system. The RL recorded is linear with dose-rate and dose. The stem effect due to both Cerenkov emission and photoluminescence in the fiber was also investigated with 18 MV photons and 12 MeV electrons.
Published: 2008
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18 results on '"Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD)"'

1. Assessing Long-term Treatment Benefits Using Complementary Statistical Approaches: An In Silico Analysis of the Phase III Keynote-045 and Checkmate-214 Immune Checkpoint Inhibitor Trials

2. Cancer de la vessie localement avancé ou métastatique : identification des freins et leviers du parcours des patients en France

3. Preliminary tolerance analysis of adjuvant chemotherapy in older patients after resection of stage III colon cancer from the PRODIGE 34-FFCD randomized trial

4. Nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial

5. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial

6. Cabozantinib-nivolumab sequence in metastatic renal cell carcinoma: The CABIR study

7. A Phase II Multicenter Trial on High-Dose Vitamin D Supplementation for the Correction of Vitamin D Insufficiency in Patients with Breast Cancer Receiving Adjuvant Chemotherapy

8. PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

9. Clinical and biological characteristics of leukemia cutis in chronic lymphocytic leukemia: A study of the French innovative leukemia organization (FILO)

10. Feasibility and efficacy of a supervised home-based physical exercise program for metastatic cancer patients receiving oral targeted therapy: study protocol for the phase II/III - UNICANCER SdS 01 QUALIOR trial

11. Impact of iterative reconstructions on image quality and detectability of focal liver lesions in low-energy monochromatic images

12. PD-L1 expression and pattern of immune cells in pre-treatment specimens are associated with disease-free survival for HR-NMIBC undergoing BCG treatment

13. Traitement des oligometastases et oligoprogression

14. OC-0284: First results of the French cohort ANABASE : treatment and outcome in non-metastatic anal cancer

15. Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations

16. 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

17. Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18 F-Misonidazole PET/CT in Patients with Non–Small Cell Lung Carcinoma (RTEP5 Study)

18. Feasibility of Fibered Monitoring System for Pulsed Dose-Rate Facilities Based on Radioluminescence of SrS:Ce,Sm Phosphor

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