Objectives: This study compared the cost and quality of life (QoL) of 407 advanced colorectal cancer patients, randomly assigned to receive LV5FU2 followed by FOLFOX6 (sequential strategy) or FOLFOX6 followed by FOLFIRI (combination strategy). Methods: Costs were compared from the French health insurance perspective, until the end of the second line of treatment. Consumed resources, collected during the trial, included medicines, hospitalizations, examinations, and transportation. Valuations were made using 2009 and 2016 tariffs. QoL was assessed using the QLQ-C30 questionnaire and clinically significant variations were searched. Results: In 2009, the mean cost per patient was significantly lower for the sequential strategy compared to the combination strategy (18,061€ and 23,119€, p = 0.001). In 2016, the difference was no longer significant (16,876€ and 18,090€, p = 0.41) because oxaliplatin and irinotecan became generics. The QoL analysis (292 patients) showed that there was significantly less improvement of global health status in the sequential strategy than in the combination strategy (29% and 42%; p = 0.02) during first-line therapy. No significant differences were observed for emotional functioning (p = 0.45) and physical functioning (p = 0.07) or during second-line therapy. Conclusion: The choice to treat patients with advanced colorectal cancer using one or the other strategy cannot be based on costs or QoL.

The original manuscript did not include the list of PETACC8 investigators. The names are repeated below. PETACC-8 study investigators Country Group(s), Coordinator(s) Principle investigator(s) (Centre) Austria Austrian Breast and Colorectal cancer Study Group (ABCSG), Joseph Thaler Josef Thaler (KlinikumKreuzschwestern Wels, Wels); Richard Greil (LKH Salzburg); Johannes Gaenzer (BKH Hall in Tirol, Hall in Tirol); Wolfgang Eisterer (University Klinik Innsbruck, Innsbruck); JoergTschmelitsch (KH BarmherzigeBrüder St. Veit / Glan) Felix Keil (LKH Leoben, Leoben); HellmutSamonigg (Landeskrankenhaus Graz MedizinischeUniversitätsklinik, Graz); August Zabernigg (BKH Kufstein, Kuftstein); Franz Schmid (LKH Bregenz, Bregenz); Günther Steger (UniversitätsklinikfürInnereMedizin I, Wein); Robert Steinacher (LKH Wolfsberg, LKH); Johannes Andel (LKH Steyr, Steyr); BjörnJagdt, (a.ö.Krankenhaus d. Barmherz. Schwest. Ried, Ried); Alois Lang (LKH Rankweil, Rankweil), Michael Fridrik (AKH Linz, Linz); Reinhold Függer (A.ö. Krankenhaus d. Elisabethinen Linz); Friedrich Hofbauer (LKH Oberpullendorf, Oberpullendorf); EwaldWoell (KH St. VinzenzZams, Zams); DietmarGeissler (LKH Klagenfurt, Klagenfurt); Alfred Lenauer (KH Wiener Neustadt, Wiener Neustadt); Manfred Prager (A.ö. KH Oberwart, Oberwart) Belgium Belgian Group of Digestive Oncology (BGDO), Jean-Luc Van Laethem and Eric Van Cutsem Geert D'Haens (Imelda Ziekenhuis, Bonheiden); Gauthier Demolin (Clinique St-Jospeh, Liège); Joseph Kerger (CliniquesUniversitaires de Mont-Godinne U.C.L. Yvoir); Guido Deboever (A. Z. St-Jozef, Oostende); Gilbert Ghillebert (Heilig Hart Ziekenhuis, Roeselare); Marc Polus (C. H. U. Sart-Tilman, Liège); Eric Van Cutsem (University Hospitals, Leuven); Hassan RezaieKalantari (C. H. Peltzer-La Tourelle, Verviers); Thierry Delaunoit (Centre Hospitalier de Jolimont-Lobbes, La Louvière); Jean Charles Goeminne (Clinique et Maternité Sainte-Elisabeth, Namur); Marc Peeters (UniversitairZiekenhuis Gent, Gent); Philippe Vergauwe (AZ Groeninge-Campus Kennedylaan, Kortrijk); GhislainHoubiers (Centre médical de L'Avenue, Liege); Yves Humblet (CliniquesUniversitaires Saint-Luc, Brussels); Jos Janssens (St-Elisabeth Ziekenhuis, Turnhout); Dirk Schrijvers (ZNA Middelheim, Antwerpen); Erik Vanderstraeten (AZ Maria Middelares, Gent); Jean-Luc Van Laethem (ULB HôpitalErasme, Brussels); Jan Vermorken (UZ Antwerpen, Edegem); Daniel Van Daele (Clinique Nôtre-Dame de Grâce, Gosselies); Michel Ferrante (AZ Sint-Maarten, Mechelen); Frederic Forget (Centre Hospitalier de l'Ardenne, Libramont); Alain Hendlisz (Jules Bordetinstituut, Brussels) Denmark Lone Nørgård Petersen MetteYilmaz (Aalborg Sygehus-AfsnitSyd, Aalborg); Svend Erik Nielsen (Hillerød Hospital, Hillerød); LeneVestermark (Odense Universitets Hospital, Odense); Jim Larsen (Roskilde Amtssygehus, Roskilde) France Fédération Francophone de Cancérologie Digestive (FFCD), Jean François Seitz; Fédération Nationale des Centres de Lutte Contre le Cancer (UNICANCER), Marc Ychou; Fédération Nationale des Centres de Lutte Contre le Cancer Association Européenne de Recherche en Oncologie (AERO), AymanZawadi Mohamed-AymanZawadi (Centre Hospitalier Les Oudairies, La Roche sur Yon); Olivier Bouche (CHU de Reims, Hopital Robert Debre, Reims); Laurent Mineur (Institut Sainte Catherine, Avignon); JaafarBennouna-Louridi (CRLCC René Gauducheau, St Herblain); Louis Marie Dourthe, (Clinique Sainte Anne, Strasbourg); Marc Ychou (Centre Regional Val d'Aurelle Paul Lamarque, Montpellier); Eveline Boucher (CRLC Eugène Marquis, Rennes); Julien Taieb (Hôpital Européen Georges Pompidou, Paris); Denis Pezet (CHU Estaing, Clermond Ferrand); FrancoiseDesseigne (Centre LeonBerard, Lyon); Michel Ducreux (Institut Gustave Roussy Villejuif); Patrick Texereau (HopitalLayne, Mont-de-Marsan); Laurent Miglianico (Centre Hospitalier Privé Saint- Grégoire (Rennes), Saint-Grégoire); Philippe Rougier (Hôpital Européen Georges Pompidou, Paris); Serge Fratte (Centre Hospitalier de Belfort-Montbeliard, Belfort); Charles-Briac Levache (Polyclinique Francheville, Perigueux); Yacine Merrouche, (Institut de Cancerologie de la Loire, Saint-Priest-En-Jarez); Stephen Ellis (Clinique Saint Pierre, Perpignan); Christophe Locher (CH Meaux, Meaux); Jean-FrancoisRamee (Centre Catherine de Sienne, Nantes); Claire Garnier (UMGEC-Institut Daniel Hollard, Grenoble); Frederic Viret (Institut Paoli Calmettes, Marseille); Bruno Chauffert (Centre Georges François Leclerc, Dijon); Isabelle Cojean-Zelek (Hopital Croix Saint Simon, Paris); Pierre Michel (Hopital Charles Nicolle, Rouen); Cedric Lecaille (Polyclinique Bordeaux Nord Aquitaine, Bordeaux); Christian Borel (CLCC Paul Strauss, Strasbourg); Jean-FrancoisSeitz (CHU de la Timone, Marseille); Denis Smith (Groupe Hospitalier Saint-Andre, Bordeaux); Catherine Lombard-Bohas (Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon); Thierry Andre (Groupe Hospitalier Pitie-Salpetriere, Paris); Jean-Marc Gornet, (Hopital Saint Louis, Paris); Francine Fein (CHU de Besancon, Hopital Jean Minjoz, Besançon); Marie-Aude Coulon-Sfairi (Centre Hospitalier du Mans, Le Mans); Marie-Christine Kaminsky (Centre Alexis Vautrin Brabois, Vandoeuvre les Nancy); Jean-Paul Lagasse (CHR d' Orléans La Source, Orléans); Dominique Luet (CRLCC Paul Papin, Angiers); Pierre-Luc Etienne (Clinique Armoricaine de Radiologie, Saint-Brieux); Mohamed Gasmi (Hopital Nord de Marseille, Marseille); AndreVanoli (Clinique Ste-Marie, Chalon Sur Saone); Suzanne Nguyen (Centre Hospitalier de Beauvais, Beauvais); Thomas Aparicio (Hôpital Bichat, Paris); Hervé Perrier (Hopital Saint Joseph, Marseille); Noel Stremsdoerfer (Hopital Pierre Oudot, Bourgoin-Jallieux); Philippe Laplaige (Clinique Saint Côme, La Chaussée St Victor); Dominique Arsene (CHU de Caen, Caen); Dominique Auby (Hôpital Robert Boulin, Libourne); Laurent Bedenne (Hopital du Bocage, Dijon); Romain Coriat (Hopital Cochin, Paris); Bernard Denis (Hopital Pasteur, Colmar); Patrick Geoffroy (Clinique Saint-Vincent, Epernay); Gilles Piot (Clinique des Ormeaux, Le Havre); Yves Becouarn (CHU de Bordeaux, Bordeaux); Gilbert Bordes (Centre Hospitalier de Digne Les Bains, Digne Les Bains); GaelDeplanque (Hopital Saint Joseph, Paris); Olivier Dupuis (Clinique Victor Hugo, Le Mans); FredericFruge (CHU Poitiers-Hôpital la Milétrie, Poitiers); Rosine Guimbaud (HopitalPurpan,Toulouse); Thierry Lecomte (Hopital Trousseau - CHU de Tours, Tours); Gérard Lledo (Hopital Prive Jean Mermoz, Lyon); IradejSobhani (Hôpital Henri Mondor (Gastro-Entérologie), Créteil); AmaniAsnacios (Hopital Antoine Beclere, Clamart); Ahmed Azzedine (Boulat, Michel, Avignon); Christophe Desauw (Hopital Saint Vincent de Paul-GHICL Lille, Lille); Marie-Pierre Galais (Centre François Baclesse, Caen); Dany Gargot (Centre Hospitalier de Blois, Blois); You-Heng Lam (Hopital de Cholet, Cholet); AbakarAbakar-Mahamat (Hopital l'Archet II, Nice); Jean-FrancoisBerdah (Clinique Sainte Marguerite, Hyères); Sylviane Catteau (Hopital Duchenne, Boulogne sur Mer); Marie-Christine Clavero-Fabri (Clinique Hartman, Levallois Perret); Jean-FrancoisCodoul (Hopital de Draguignan, Draguignan); Jean-Louis Legoux (Hôpital Haut Levêque, Pessac); Denis Goldfain (Centre Hospitalier General de Dreux, Dreux); Pierre Guichard (Clinique des quatre Pavillons, Lormont); Denis Pere Verge (Hôpital de la Croix Rousse (Gastroentérologie), Lyon); Jocelyne Provencal (Centre Hospitalier d'Annecy, Pringy); Bruno Vedrenne (Hopital E. Muller, Mulhouse); Catherine Brezault-Bonnet (Hopital de Rambouillet, Rambouillet); Denis Cleau (Centre Hospitalier Intercommunal de Vesoul, Vesoul); Jean-Paul Desir (Clinique Pole Sante Republique, Clermont-Ferrand); David Fallik (Polyclinic Jeanne d'Arc Gien); Bruno Garcia (Clinique de Courlancy, Reims); Marie-Hélène Gaspard (Clinique Claude Bernard, Albi); Dominique Genet (Centre de CancerologieChenieux, Limoges); Johannes Hartwig (Infirmerie Protestante de Lyon, Caluire et Cuire); Yves Krummel (Centre Hospitalier Selestat, Selestat); Tamara MatysiakBudnik (CH de Nantes Hotel Dieu, Nantes); Vanessa Palascak-Juif (Hopital de Hautepierre, Strasbourg); HarizoRandrianarivelo (Centre FredericJoliot, Rouen); Yves Rinaldi (Clinique Clairval, Marseille); Albert Aleba (Centre Hospitalier de Niort, Hopital Georges Renon, Niort); Ariane Darut-Jouve (Centre d'oncologie et Radiotherapie, Dijon); Aimery de Gramont (Hopital Saint Antoine, Paris); Herve Hamon (Centre Hospitalier de Valence, Valence); FredericWendehenne (Clinique Charcot, Sainte-Foy-les-Lyon) Germany ArbeitsgemeinschaftInternistischeOnkologie (AIO), GunnarFolprecht Axel Matzdorff (Caritasklinik St. Theresia, Saarbruecken); Michael Konrad Stahl (Kliniken Essen-Mitte–PS, Essen); Wolfgang Schepp (KKH MuenchenBogenhausen, Muenchen); Martin Burk (Klinikum der Stadt Hanau, Hanau); Lothar Mueller (OnkologischeSchwerpunktpraxis, Leer); Gunnar Folprecht (Universitaetsklinikum Carl Gustav Carus, Dresden); Michael Geissler (StaedtischeKliniken Esslingen, Esslingen); Luisa Mantovani-Loeffler (StaedtischesKlinikum St. Georg Leipzig, Leipzig); Thomas Hoehler (Prosper-Hospital, Recklinghausen); Walter Asperger (Krankenhaus St. Elisabeth und St. Barbara, Halle); HendrikKroening (Gemeinschaftspraxis, Magdeburg); Ludwig Fischer von Weikersthal (MVZ Gesundheitszentrum St. Marien GmbH, Amberg); Stefan Fuxius (Onkologische Praxis, Heidelberg); Matthias Groschek (Haematologisch-Onkologische Praxis Wuerselen, Wuelselen); Johannes Meiler, TanjaTrarbach (Universitaetsklinikum Essen, Essen); Jacqueline Rauh (GemeinschaftspraxisArdeystrasse, Witten); Nicolas Ziegenhagen, Albrecht Kretzschmar (Helios-Kliniken Berlin, Berlin); UllrichGraeven (Kliniken Maria Hilf GmbH, Moenchengladbach); ArndNusch (Onkologische Praxis, Velbert); Goetz von Wichert (Universitaetsklinikum, Ulm); Ralf-Dieter Hofheinz (Klinikum der Stadt Mannheim, Mannheim); Gerhard Kleber (Ostalb-Klinikum Aalen, Aalen); Karl-Heinz Schmidt (Johanniter-KrankenhausRheinhausen, Duisberg); Ursula Vehling-Kaiser (Gemeinschaftspraxis, Landshut); Claudia Baum, JochenSchuette (Marien Hospital Duesseldorf GmbH, Duesseldorf); Georg Martin Haag (Universitaetsklinikum Heidelberg, Heidelberg); Wilhelm Holtkamp (Ammerland-Klinik GmbH, Westerstede); JochenPotenberg (Evangelisches Waldkrankenhaus, Berlin); Tobias Reiber (Praxis fuer Haematologie/Onkologie, Freiberg); Georg Schliesser (Praxis fuerHaematologie und Onkologie, Giessen); Hans-Joachim Schmoll (Martin-Luther-Universitaet Halle-Wittenberg, Halle); Wolfgang Schneider-Kappus (Arztpraxis, Ulm); Wolfgang Abenhardt (Onkologie Praxis imElisenhof, Muenchen); Claudio Denzlinger (Marienhospital Stuttgart, Stuggart); Jan Henning, BartschtMarxsen (Universitaetsklinikum Schleswig-Holstein, Luebeck); Hans GuenterDerigs (StaedtischeKliniken Frankfurt-Hoechst, Frankfurt); Helmut Lambertz (Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen); Ingulf Becker-Boost (MVZ Duisburg Sued GmbH, Duisburg); Karel Caca (Klinikum Ludwigsburg, Ludwigsburg); Christian Constantin (Kliniken Lippe-Lemgo GmbH, Lemgo); Thomas Decker (Gemeins chaftspraxis, Ravensburg); Henning Eschenburg (Internistische Gemeinschaftspraxis, Guestrow); SigrunGabius (Gemeinschaft spraxis, Rosenheim); HolgerHebart (KlinikumSchwaebisch Gmuend-Stauferklinik, Mutlangen); Albrecht Hoffmeister (Universitaetsklinikum Leipzig, Leipzig); Heinz-August Horst (Universitaetsklinikum Schleswig-Holstein-Campus Kiel, Kiel); Stephan Kremers (Caritas-Krankenhaus, Lebach); MalteLeithaeuser (Universitaetsmedizin Rostock, Rostock); Sebastian Mueller (AmbulantesOnkologieZentrum, Ansbach); Siegfried Wagner (KlinikumDeggendorf, Deggendorf); SeverinDaum (Charité Universitaetsmedizin Berlin-Campus CharitéMitte, Berlin); Frank Schlegel (St. Antonius-Hospital, Eschweiler); Martina Stauch (OnkologischeSchwerpunktpraxis, Kronach); Volker Heinemann (Klinikum der Ludwig-Maximilians-Universitaet, Muenchen) Italy Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD), Roberto Labianca; Gruppo Oncologico dell'Italia Meridionale (GOIM), Giuseppe Colucci; Istituto Oncologico Romagnolo (IOR), Dino Amadori; Gruppo Cooperativo Chirurgico Italiano (GOCCI), Enrico Mini; Gruppo Oncologico Nord Ovest (GONO), Alfredo Falcone; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC), Corrado Boni Evaristo Maiello (IRCCS Casa Sollievo della sofferenza, San Giovanni Rotondo); Luciano Latini (Ospedale di Macerata, Macerata); Alberto Zaniboni (Fondazione Poliambulanza Istituto Ospedaliero, Brescia); Dino Amadori (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola); Giuseppe Aprile (Az. Policlinico Universitario di Udine, Udine); Sandro Barni (Azienda Ospedaliera Treviglio-Caravaggio, Treviglio); Rodolfo Mattioli (Ospedale Santa Croce ASUR 3, Fano); Andrea Martoni (Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Ma, Bologna); Rodolfo Passalacqua (Azienda Ospedaliera Istituti Ospitalieri di Cremona, Cremona); Mario Nicolini, Enzo Pasquini (Ospedale Cervesi, Cattolica); Carla Rabbi, Enrico Aitini (Azienda Ospedaliera Carlo Poma, Mantova); Alberto Ravaioli (Ospedale degli Infermi, Rimini); Carlo Barone (Policlinico Universitario Agostino Gemelli, Roma); Guido Biasco (Ospedale Marcello Malpighi Policlinico Sant'Orsola, Bologna); Stefano Tamberi, Angelo Gambi (Ospedale Degli Infermi, Faenza); Claudio Verusio (Ospedale di Saronno, Saronno); Marina Marzola, Giorgio Lelli (Azienda Ospedaliera Universitaria Arcispedale Sant'Anna, Cona (Ferrara)); Corrado Boni (A.O. Arcispedale Santa Maria Nuova, Reggio Emilia); Stefano Cascinu (Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona); Paolo Bidoli, Massimo Vaghi (Azienda Ospedaliera San Gerardo, Monza); Giorgio Cruciani (Ospedale Umberto I, Luggo); Francesco Di Costanzo (Azienda Ospedaliera Universitaria Careggi, Firenze); Alberto Sobrero (Azienda Ospedaliera San Martino, Genoa); Enrico Mini (A.O. Universitaria Careggi, Firenze); Roberto Petrioli (A.O.U. Senese Policlinico Santa Maria alle Scotte, Siena); Massimo Aglietta (Istituto per la Ricerca e la Cura del Cancro, Candiolo); Oscar Alabiso (Ospedale Maggiore della Carità, Novara); Federico Capuzzo, Alfredo Falcone (Presidio Ospedaliero di Livorno, Livorno); Domenico Cristi Corsi (Ospedale "S. Giov. Calibita" Fatebenefratelli. Roma); Roberto Labianca (Ospedali Riuniti di Bergamo, Bergamo); Stefania Salvagni (Azienda Ospedaliera di Parma, Parma); Silvana Chiara (Istituto nazionale per la ricerca sul cancro, Genova) Libero Ciuffreda (A.O. San Giovanni Battista, Torino); Francesco Ferraù (Azienda Ospedaliera San Vincenzo, Taormina); Francesco Giuliani (Istituto Oncologico Giovanni Paolo II IRCCS, Bari); Sara Lonardi (IOV-Istituto Oncologico Veneto IRCCS, Padova); Nicola Gebbia (Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone, Palermo); Giovanni Mantovani (Università di Cagliari-Presidio Policlinico Monserrato, Monserrato) Portugal Gruppo Cooperativo do Cancro Digestivo da Associação Portuguesa de InvestigaçãoOncológica (GCCD, APIO), Evaristo Sanches Evaristo Sanches (InstitutoPortuguês de Oncologia do Porto Francisco Gentil, Porto); Juan Carlos Mellidez (Hospital Distrital de Aveiro, Aveiro); Pedro Santos (Hospital SãoSebastião, EPE, Santa Maria da Feira); Joao Freire (InstitutoPortugues de Oncologia, Lison); Cristina Sarmento (Hospital de Sao Joao, Porto); Luis Costa (Hospital de Santa Maria, Lisbon); Antonio Moreira Pinto (Hospital Geral de Santo Antonio, Porto); Sergio Barroso (Hospital Distrital de Beja, Beja); Jorge Espirito Santo (Hospital do Barreiro, Barreiro); FátimaGuedes (Hospital DistritalFigueira da Foz, EPE, Figueira da Foz); Amélia Monteiro (Hospital SãoTeotónio, EPE, Viseu); Anabela Sa (Hospitais da Universidade de Coimbra, Coimbra); Irene Furtado (Hospital Distrital de Faro, Faro) Spain GrupoEspañol para elTratamiento de losTumoresDigestivos (TTD), Josep Tabernero Ramon Salazar (ICO ĺHospitalet Hospital Duran iReynals, Barcelona); EnriqueArandaAguilar (Hospital Reina Sofia, Cordoba); Fernando Rivera Herrero (Hospital Universitario Marques de Valdecilla, Santander); Josep Tabernero (Hospital. Vall d'Hebron, Barcelona); Javier Sastre Valera (Hospital Clinico San Carlos, Madrid); Manuel ValladaresAyerbes (ComplejoHospitalario Universitario A Coruña, A Coruña); Jaime FeliuBatlle (Hospital Universitario La Paz, Madrid); Silvia Gil (Hospital Carlos Haya, Malaga; Albert Abad Esteve (ICO Badalona-Hospital Germans Trias i Pujol, Barcelona); Carlos Garcia-Giron (Hospital Universitario de Burgos, Burgos); Guillermo Lopez Vivanco (Hospital de Cruces, Vizcaya); Antonia Salud Salvia (Hospital Universitario de Lleida Arnau de Vilanova, Lleida); Vicente Alonso Orduña (Hospital Miguel Servet, Zaragoza); Ruth Vera Garcia (ComplejoHospitalario de Navarra, Pamplona); Javier Gallego (HGU de Elche, Elche-Alicante); BartomeuMassutiSureda (Hospital General Universitario de Alicante, Alicante); Jordi Remon (Hospital de Mataro, Barcelona); Maria Jose Safont Aguilera (Hospital General Universitario de Valencia, Valencia); Luis CireraNogueras (Hospital Mutua de Terrassa, Barcelona); BernadoQueralt Merino (Hospital Universitari de Girona Dr Josep Trueta, Girona); Cristina Gravalos Castro (Hospital 12 de Octubre, Madrid); Purificacion Martinez de Prado (Hospital de Basurto, Bilbao); Carlos PijaumePericay (ConsorciHospitalariParcTauli, Barcelona); Manuel ConstenlaFigueiras (Hospital Provincial de Pontevedra, Pontevedra); InmaculadaGuasch Jordan (Hospital Sant Joan de Deu de Manresa, Manresa); Maria Jose GomeReina (Hospital del Mar, Cadiz); Amelia Lopez-Ladron Garcia (Hospital ElTomillar-NtraSra de Valme, Sevilla); Antonio Arrivi Garcia-Ramos (Fundacion Hospital Son Llatzer, Palma Mallorca); Andres Cervantes (Hospital Clinico Universitario de Valencia, Valencia); Carlos Fernandez Martos (InstitutoValenciano de Oncologia, Valencia); Eugenio MarcuelloGaspar (Hospital de la Santa Creu i Sant Pau, Barcelona); Ines Cabezas Montero (Hospital Universitario Sant Joan de Reus, Tarragona); Pilar EscuderoEmperador (Hospital Clinico Universitario Lozano Blesa, Zaragoza); Ana Leon Carbonero (Fundacion Jimenez Diaz, Madrid); Manuel Gallen Castillo (Hospital del Mar, Barcelona); Teresa Garcia Garcia (Hospital MoralesMeseguer, Murcia); Jose Garcia Lopez (Hospital Universitario Ramón y Cajal, Madrid); EncarnacionGonzalezFlores (Hospital Virgen de las Nieves Ruiz de Alda, Granada); Monica GuillotMorales (Hospital Son Espases, Palma de Mallorca); Marta LlanosMuñoz (Hospital Universitario de Canarias, Santa Cruz de Tenerife); Ana López Martín (Hospital Severo Ochoa); Joan Maurel (Hospital Clinic i Provincial, Barcelona); Juan Carlos Camara (Fundacion Hospital Alcorcon, Madrid); Rosario Dueñas Garcia (Hospital Ciudad de Jaen, Jaen); Mercedes Salgado (ComplejoHospitalario Ourense, Ourense); Isabel HernandezBusquier (Hospital ProvincialCastellon, Castellon); Teresa Checa Ruiz (Instituto de Oncologia Corachan, Barcelona); Adelaida LacastaMuñoa (Hospital. de Donostia, San Sebastian); MiquelNogueAliguer (Hospital General de Vic, Vic); Amalia Velasco Ortiz de Taranco (Hospital Universitario de La Princesa, Madrid); Miguel Mendez Ureña (Hospital General de Mostoles, Mostoles); Ferran Losa Gaspa (Consorci Sanitari CreuRoja, Barcelona); Jose Juan Ponce (Hospital Virgen de losLirios, Alicante); Carlos Bosch Roig (Hospital Universitario. Dr.Peset, Valencia); Pedro Valero Jimenez (Clínica Infanta Luisa, Sevilla); Antonio GalanBrotons (Hospital Sagunto, Sagunto); Santiago AlbiolRodriguez (Hospital Espiritu Santo, Barcelona); Jose Ales Martinez (Hospital RuberInternacional de Madrid, Madrid); Liliana Canosa Ruiz (Hospital Torrecardenas, Almeria); Margarita CentellesRuiz (Hospital SagratCor, Barcelona) United Kingdom John Allen Bridgewater John Bridgewater (North Middlesex University Hospital NHS Trust, London); Rob Glynne-Jones (Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, London); SaadTahir (Broomfield Hospital, Chelmsford); TamasHickish (Poole Hospital NHS Trust, Poole and Bournemouth Hospital, Bournemouth); Jim Cassidy (Beatson West of Scotland Cancer Centre, Glasgow); Leslie Samuel (Aberdeen Royal Infirmary, Aberdeen) Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial datasetAnnals of OncologyVol. 25Issue 12PreviewThe prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial. Full-Text PDF Open Archive

Background: Kohne's prognostic classification has been previously proposed, based on performance status, alkaline phosphatase level, number of metastatic sites and white blood cells count.Aims: To identify prognostic factors for survival and to assess the validity of Kohne's classification, in the era of targeted biotherapies, in patients treated with chemotherapy for non resectable metastatic colorectal cancer.Methods: A total of 290 consecutive patients were retrospectively identified in all gastroenterology units of one French county, between 2004 and 2008. Univariate and multivariate analysis for overall survival were performed using pre-treatment patient characteristics.Results: All data were available for prognostic categorization in 133 patients. Median survival was 22.1 months. The distribution and median survival for Kohne's prognostic groups were as following: good (n=73; 24.8 months), intermediate (n=35; 24.2 months), and poor (n=25; 7.0 months). The survival difference was significant between good and poor prognostic groups (p<0.01) and between intermediate and poor prognostic groups (p<0.01), but not between good and intermediate prognostic groups (p=0.5). The two independent prognostic factors of survival in multivariate analysis were performance status 0/1 (p<0.01) and white blood cells count <10 x 10(9)/L (p<0.01).Conclusions: The relevance of Kohne's classification is questioned. A simplified score could be validated by largest studies, based on white blood cells count and performance status. (C) 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer.Methods In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials. gov, NCT00126256.Findings 205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10.5 months (95% CI 9.6-11.5) in the sequential group and 10.3 months (9.0-11.9) in the combination group (hazard ratio 0.95, 95% CI 0.77-1.16; p=0.61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p<0.0001) and non-haematological adverse events (26 events vs 186 events; p<0.0001) occurred in the sequential group than in the combination group.Interpretation Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer.Funding Sanofi-Aventis France.

Adherence was not predicted by specialty, expert status, practice type or region, or HBV patient load.Conclusions: Respondents endorsed most -but not all -CDC-supported HBV screening practices.Lower adherence was predicted by specific & modifiable KAB profiles, and by younger age.Future efforts to improve adherence might be optimally effective if they are targeted to trainees, emphasize the importance of obtaining appropriate social & sexual histories in high risk patients, & inform that HBV is a predominantly heterosexually transmitted infection.

Objective - The aim of this retrospective study was to compare clinical, biological, and histological features and treatment response in 115 patients with overlap syndrome (05), autoimmune hepatitis (AIH) or primary biliary cirrhosis (PBC).Methods - Consecutive patients with AIH, PBC or OS followed between 1984 and 2005 in five different centers were included. All data were re-evaluated using current diagnostic criteria of each disease.Results - Fifteen patients had OS (13 females), 48 AIH (40 females) and 52 PBC (49 females). Patients with OS were significantly younger than patients with PBC (median age: 44 vs 59 years). Jaundice (20%) and pruritus (20%) were the main initial symptoms in OS. Patients with OS had serum transaminase and gamma-globulin levels significantly higher than patients with PBC; serum alkaline phospkatase, gamma-glutamyl-transpeptidase and IgM levels were significantly higher in OS than in patients with AIH. Histological analysis showed moderate or severe piecemeal necrosis in 86% and destructive cholangitis in 93% in OS group. Among 11 patients with OS treated with ursodeoxycholic acid (UDCA) or immunosuppressors alone, only 6 had a complete biochemical response. In contrast, all patients with 05 receiving combined therapy, as first or second line, responded, 5 patients to the combination corticoste-roids-azathioprine-UDCA and 2 to the combination cyclosporine-UDCA.Conclusion - OS is not rare and accounts for 13.9% of patients with autoimmune liver disease in our series. Combination of immunosuppressors and UDCA appears the most efficient treatment in these patients.

This controlled trial was designed to evaluate the prophylactic effect of nadolol on gastrointestinal bleeding in cirrhotic patients with large oesophageal varices who had never bled. Nadolol or placebo was given randomly to two groups of 53 patients. The percentage of patients free of gastrointestinal bleeding 1 year after inclusion in the study was 83 ± 6% (mean ± S.D.) in the nadolol group and 80 ± 6% in the placebo group. In the nadolol and placebo groups, 40 and 47 patients, respectively, were compliant, i.e., took nadolol or placebo continuously. The percentage of patients who were free of bleeding 1 year after inclusion was 97 ± 3% in the subgroup of compliant nadolol patients. This percentage was significantly higher than that of patients who were free of bleeding in the placebo group (P < 0.03) as well as in the subgroup of compliant placebo patients (77 ± 6%; P < 0.02). We concluded that, although there was no overall significant effect of nadolol on the risk of bleeding in cirrhotic patients in good condition with large oesophageal varices, this study suggests that nadolol reduced the risk of bleeding in compliant patients.

The acute effects of betaxolol (10 mg, intravenously), a new cardioselective beta-blocker, and propranolol (15 mg, intravenously) on splanchnic and systemic circulations were studied in two matched groups of six patients with portal hypertension due to cirrhosis. Similar decreases in hepatic venous pressure gradient and azygous blood flow--an estimation of superior portosystemic shunts--were observed after both drugs, whereas hepatic blood flow was not modified. The decreases in heart rate and cardiac index were also similar after betaxolol and propranolol. Both drugs induced a significant decrease in the fraction of cardiac output flowing through superior portosystemic shunts. These findings confirm that the marked effect of beta-adrenoceptor blocking agents on splanchnic circulation results both from the reduction in cardiac output and from a vasoconstriction of the portal vein territory, and demonstrate that this vasoconstriction of the portal vein area does not necessitate a beta 2-blocking activity of the drug. The similar efficiency of the two agents in decreasing the hyperkinetic circulation suggests that betaxolol merits further long-term study in the pharmacologic treatment of portal hypertension.

In patients with cirrhosis, endogenous catecholamines may influence the circulatory effects of propranolol. We intended to evaluate the interaction of adrenaline and propranolol on azygos blood flow, an estimate of blood flow in the superior portosystemic collateral circulation. We investigated 6 patients with cirrhosis, 5 with good liver function, receiving an intravenous infusion of adrenaline (50 ng/kg/min) before and after administration of propranolol. The median value for baseline azygos blood flow was increased from 700 ml/min (range 340-1 470 ml/min) to 1 050 (range 570-1 840 ml/min) with adrenaline alone (P less than 0.05), and decreased to 610 ml/min (range 260-1 190 ml/min) with propranolol alone (P less than 0.05). The infusion of adrenaline given after propranolol further reduced azygos blood flow to a median value of 530 ml/min (range 200-730 ml/min) (P less than 0.05). Thus, following beta-adrenergic blockade, there is a reversal of the effects of adrenaline on azygos blood flow, which corresponds to a potentiation of the effects of propranolol. Similar endogenous adrenaline-propranolol interactions may play a role in preventing recurrent variceal bleeding in cirrhotic patients.

Systemic and splanchnic haemodynamics were studied in patients with cirrhosis who had been classified in three groups (A, B, and C) according to the degree of liver failure (modified Pugh's classification). In patients of group A, cardiac index was significantly lower than that of group C and systemic vascular resistance was higher, but not significantly so, than that of patients with liver failure. Wedged hepatic venous pressure was significantly lower in the former group than in the latter. In patients in group B, corresponding values fell between those of groups A and C. Azygos blood flow averaged 0.477 +/- 0.242 l/min (mean +/- SD) in group A and it was significantly lower than in groups B and C (0.642 +/- 0.224 and 1.061 +/- 0.476 l/min, respectively). In the three groups, acute administration of propranolol induced statistically significant changes in systemic and splanchnic haemodynamics. In patients of group C but not of group B, the mean value of azygos blood flow after propranolol remained significantly higher than in group A. Moreover, the fraction of azygos blood flow to cardiac output decreased in groups A and B while slightly increased in group C. This study shows that in patients with cirrhosis, the degree of liver failure may be a determinant for the haemodynamic responses to drugs acting on portal hypertension.

To assess the influence of vasopressin on splanchnic and renal circulatory changes induced by haemorrhage in portal hypertension, we studied 4 groups of 7 rats with chronic portal vein stenosis. Two groups received saline (C and H) and two groups vasopressin, 0.01 IU/kg/min (VP and VP-H). Ten minutes after starting drug infusion, group H and VP-H animals were allowed to bleed from the superior mesenteric vein. Both haemorrhage and vasopressin alone, decreased portal venous tributary blood flow and pressure but their association was not additive (as reflected by comparable bleeding rate in groups H and VP-H). By contrast, vasopressin increased renal perfusion in bleeding and non-bleeding animals whereas haemorrhage alone decreased renal perfusion. These results indicate that the effects of vasopressin on the splanchnic circulation in bleeding anaesthetized animals differ from the effects observed when blood volume is normal. Therefore, in patients with cirrhosis the effects of vasopressin during bleeding might also differ from those observed in patients in stable condition.

The haemodynamic effect of sudden termination of propranolol therapy was studied in sham-operated and portal hypertensive rats. All animals were injected with propranolol (20 mg/kg/day) or saline i.p. for 10 days, then had an isoproterenol infusion test performed 48 h or 72 h after cessation of injections. The dose of isoproterenol required to increase the heart rate by 50 beats/min (CD50), was significantly lower in both sham-operated and portal hypertensive rats at 48 h after propranolol withdrawal. Maximum chronotropic response (Rmax), was significantly higher only in portal hypertensive rats at 48 h after propranolol withdrawal. These results show the existence of a transient β-adrenergic hypersensitivity state following propranolol withdrawal in normal and portal hypertensive rats.

To determine the effect of pentobarbital sodium anesthesia on the rat with portal hypertension due to portal vein stenosis, four groups of rats were studied. Cardiac output and regional blood flow were measured by radioactive microspheres in anesthetized and conscious sham-operated and portal-hypertensive rats. Anesthesia markedly decreased cardiac output in both sham-operated (109.7 +/- 4.6 vs. 77.8 +/- 1.4 ml/min, P less than 0.001) and portal-hypertensive rats (130.1 +/- 7.6 vs. 93.8 +/- 5.3 ml/min, P less than 0.01). In spite of this diminution in cardiac output, pentobarbital did not significantly change absolute blood flow values of splanchnic organs in either group. However, the fractions of cardiac output perfusing the splanchnic organs were significantly increased by pentobarbital in both groups because of the decrease in cardiac output: sham operated, anesthetized, 22.86 +/- 1.19% vs. conscious, 14.83 +/- 1.02%, P less than 0.001; and portal hypertensive, anesthetized, 26.67 +/- 0.71% vs. conscious, 19.07 +/- 1.44%, P less than 0.001. The hyperdynamic circulation of the portal vein-stenosed rat compared with the sham-operated rat continued to manifest itself with significantly increased portal pressure, cardiac output, and splanchnic blood flow, whether the animal was anesthetized or awake. We conclude that, despite marked hemodynamic changes induced by pentobarbital, the rat with portal vein stenosis remains a useful experimental model of portal hypertension.