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Early evaluation using a radiomic signature of unresectable hepatic metastases to predict outcome in patients with colorectal cancer treated with FOLFIRI and bevacizumab
  1. Anthony Dohan1,2,3,
  2. Benoit Gallix3,4,5,
  3. Boris Guiu6,7,
  4. Karine Le Malicot8,9,
  5. Caroline Reinhold3,
  6. Philippe Soyer1,2,
  7. Jaafar Bennouna10,
  8. Francois Ghiringhelli11,
  9. Emilie Barbier8,9,
  10. Valérie Boige12,
  11. Julien Taieb2,13,
  12. Olivier Bouché14,
  13. Eric François15,
  14. Jean-Marc Phelip16,
  15. Christian Borel17,
  16. Roger Faroux18,
  17. Jean-Francois Seitz19,
  18. Stéphane Jacquot20,
  19. Meher Ben Abdelghani21,
  20. Faiza Khemissa-Akouz22,
  21. Dominique Genet23,
  22. Jean Louis Jouve24,
  23. Yves Rinaldi25,
  24. Françoise Desseigne26,
  25. Patrick Texereau27,
  26. Etienne Suc28,
  27. Come Lepage9,24,
  28. Thomas Aparicio2,29,
  29. Christine Hoeffel30,31
  30. for the PRODIGE 9 Investigators and PRODIGE 20 Investigators
    1. 1 Radiologie A, Assistance Publique - Hôpitaux de Paris, Cochin Hospital, Paris, France
    2. 2 Medical School, Université de Paris, Paris, France
    3. 3 Radiology, McGill University Health Centre, Montreal, Quebec, Canada
    4. 4 IRCAD, Institut Hospitalo-Universitaire, Strasbourg, France
    5. 5 Medical School, Université de Strasbourg, Strasbourg, France
    6. 6 Radiology, Hopital Saint-Eloi, Montpellier, Languedoc-Roussillon, France
    7. 7 Medical School, Université de Montpellier, Montpellier, France
    8. 8 Biostatistics, FFCD, Dijon, France
    9. 9 EPICAD, INSERM LNC-UMR 1231, University of Burgundy and Franche-Comté, Dijon, France
    10. 10 Gastroenterology and Digestive Oncology, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France
    11. 11 Medical oncology, Center GF Leclerc, Dijon, France
    12. 12 Oncologic Medicine, Institut Gustave Roussy, Villejuif, France
    13. 13 Hepatogastroenterology and GI Oncology, Assistance Publique - Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
    14. 14 Gastrointestinal Oncology Unit, CHU Reims, Reims, France
    15. 15 Pôle de Médecine, Centre Antoine-Lacassagne, Nice, France
    16. 16 Hepatogastroenterology, Saint Etienne University Hospital, Hôpital Nord, Saint Priest en Jarez, France
    17. 17 Oncology, Centre Paul Strauss, Strasbourg, Alsace, France
    18. 18 Gastroenterology, Hospital of La Roche sur Yon, La Roche sur Yon, France
    19. 19 Hepatogastroenterology and Oncology, Hopital de la Timone, Marseille, Provence-Alpes-Côte d’Azu, France
    20. 20 Oncology, Centre de Cancérologie du Grand Montpellier, Montpellier, France
    21. 21 Oncology, Centre Paul Strauss, Strasbourg, Alsace, France
    22. 22 Hepatogastroenterology, Centre Hospitalier de Perpignan, Perpignan, France
    23. 23 Medical Oncology, Clinique Francois Chenieux, Limoges, France
    24. 24 Hepatogastroenterology, University Hospital Le Bocage, Dijon, France
    25. 25 Digestive Oncology, Hopital Européen, Marseilles, France
    26. 26 Medical oncology, Centre Leon Berard, Lyon, France
    27. 27 Gastroenterology, Centre Hospitalier de Mont-de-Marsan, Mont-de-Marsan, Aquitaine, France
    28. 28 Medical oncology, Clinique Saint Jean de Languedoc, Toulouse, Midi-Pyrénées, France
    29. 29 Gastroenterology and Digestive Oncology Department, Assistance Publique - Hôpitaux de Paris, Saint-Louis Hospital, Paris, France
    30. 30 Radiology, Hopital Maison Blanche, Reims, Champagne-Ardenne, France
    31. 31 CRESTIC, Université de Reims, Reims, URCA, France
    1. Correspondence to Dr Anthony Dohan, Radiology A, Hopital Cochin, Paris 75679, France; anthony.dohan{at}aphp.fr

    Abstract

    Purpose The objective of this study was to build and validate a radiomic signature to predict early a poor outcome using baseline and 2-month evaluation CT and to compare it to the RECIST1·1 and morphological criteria defined by changes in homogeneity and borders.

    Methods This study is an ancillary study from the PRODIGE-9 multicentre prospective study for which 491 patients with metastatic colorectal cancer (mCRC) treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab had been analysed. In 230 patients, computed texture analysis was performed on the dominant liver lesion (DLL) at baseline and 2 months after chemotherapy. RECIST1·1 evaluation was performed at 6 months. A radiomic signature (Survival PrEdiction in patients treated by FOLFIRI and bevacizumab for mCRC using contrast-enhanced CT TextuRe Analysis (SPECTRA) Score) combining the significant predictive features was built using multivariable Cox analysis in 120 patients, then locked, and validated in 110 patients. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the logrank test. An external validation was performed in another cohort of 40 patients from the PRODIGE 20 Trial.

    Results In the training cohort, the significant predictive features for OS were: decrease in sum of the target liver lesions (STL), (adjusted hasard-ratio(aHR)=13·7, p=1·93×10–7), decrease in kurtosis (ssf=4) (aHR=1·08, p=0·001) and high baseline density of DLL, (aHR=0·98, p<0·001). Patients with a SPECTRA Score >0·02 had a lower OS in the training cohort (p<0·0001), in the validation cohort (p<0·0008) and in the external validation cohort (p=0·0027). SPECTRA Score at 2 months had the same prognostic value as RECIST at 6 months, while non-response according to RECIST1·1 at 2 months was not associated with a lower OS in the validation cohort (p=0·238). Morphological response was not associated with OS (p=0·41).

    Conclusion A radiomic signature (combining decrease in STL, density and computed texture analysis of the DLL) at baseline and 2-month CT was able to predict OS, and identify good responders better than RECIST1.1 criteria in patients with mCRC treated by FOLFIRI and bevacizumab as a first-line treatment. This tool should now be validated by further prospective studies.

    Trial registration Clinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029.

    Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717.

    • chemotherapy
    • clinical decision making
    • colorectal cancer
    • colorectal metastases
    • computerised image analysis
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    Footnotes

    • TA and CH contributed equally.

    • Contributors AD is the guarantor of the present work. AD designed the study, collected the data and drafted the manuscript. BG, CR, PS supervised the study and drafted the manuscript. BG, VB, JT, OB collected the data and drafted the manuscript. KLM conducted the statistical analysis and drafted the manuscript. JB, FG, EF, J-MP, CB, RF, J-FS, FK-A, DG, JLJ, YR, SJ, MBA, FD, PT, ES, CL collected the data, and edited and approved the manuscript. EB conducted the statistical analysis. TA collected the data, conducted the original studies, supervised the present study and drafted the manuscript. CH supervised the present study and drafted the manuscript.

    • Funding Fédération Francophone de Cancérologie Digestive, Ligue Nationale Contre le Cancer, ROCHE. The study was funded by Fédération Francophone de Cancérologie Digestive (FFCD). The Liguecontre le Cancer provided financial support to FFCD. ROCHE provided financial support for study management.

    • Competing interests VB reports consultingor/and advisory boards for Merck Serono, Ipsen, Prestizia, Eisai, and Bayer. DrBoige has received honoraria for Merck Serono, Sanofi, Amgen, MSD and Bayer. CL reports personal grants for boardmembership for AAA, grants from Novartis and travel grants from Ipsen Pharma,Amgen and Bayer. OB reports personalgrants for consultancy for A mgen, Merck, Roche, Bayer; payment forlectures including service onspeakers bureau for Servier, Pierre Fabre ; and travel grants from Roche,Lilly. CB reports consultingfor BMS ; payment for lectures for Merck Serono et BMS ; Paymentsfor development of educational presentations for Aztra-Zenecaand BMS; travel grants from Merck Serono and Aztra-Zeneca; Advisory Boardmembership for BMS and Aztra-Zeneca. EF reports personal grants for boardmembership for Roche, Merck and Sanofi. JB reports personal grants for boardmembership for Roche, Boehringer-Ingelheim, Astra-Zeneca, Servier and BMS;payment for lectures including service on speaker bureau for Roche,Astra-Zeneca and travel grants from Roche and BMS. JT reports personal grantsfor consultancy for Abbvie, Amgen, Baxalta, Celgene, Lilly, Merck, Roche,Servier, MSD, Pierre-Fabre and Sanofi; payment for lectures including serviceon speakers bureau for ABBVIE, Amgen, Celgene, Lilly, Merck, Roche; paymentsfor development of educational presentations for Roche and travel grants fromRoche and Merck. J-MP reports personal grants for board membership for Roche,Sanofi, Lilly Merck and Amgen; consultancy for Lilly and Roche; payments fordevelopment of educational presentations for Roche, Sanofi, Lilly Merck andAmgen; grants for his institution for board membership for Roche and Merck ;payments of grants form Merck and Roche. J-FS reports personal grants forconsultancy for Celgene, Lilly, Merck, Novartis Oncology, Pfizer, Sanofi,Roche; grants from Roche; payments for development of educational presentationsfor Amgen and Lilly; travel grants from Ipsen Pharma and Merck. F-KAreports consultancy for Sanofi as Board member and travelgrants from Roche, Bayer and Ipsen. M-BA reports consulting and travel supportfrom Amgen, Bayer, Merck, Roche, Sanofi, and Ipsen. T A reports personal grants Consultancy for Pierre Fabre; Grantsfrom Roche and Amgen; Payments for development of educational presentations forNovartis Oncology, Pfizer, Sanofi, Roche; Travel grants from Ipsen Pharma,Novartis Oncology, Sanofi, Roche.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators Dr Julien Volet (Centre Hospitalier Universitaire Robert Debré, Reims), Dr Sylvie Kirscher (Institut Sainte Catherine, Avignon), Dr Laurence Delique (Centre Hospitalier Universitaire Nancy-Brabois, Vandoeuvre les Nancy), Pr Philippe Rougier (Hôpital Européen Georges Pompidou, Paris), Dr Céline Lepere (Hôpital Européen Georges Pompidou, Paris), Dr Olivier Dubreuil (Hôpital Européen Georges Pompidou, Paris), Dr Aziz Zaanan (Hôpital Européen Georges Pompidou, Paris), Dr Guillaume Medinger (Centre Hospitalier Départemental Vendée, La Roche-Sur-Yon), Pr Antoine Adenis (Centre Oscar Lambret, Lille), Dr Farid El Hajbi (Centre Oscar Lambret, Lille), Dr Gilles Gatineau Sailliant (Centre Hospitalier, Meaux)Dr Christophe Locher (Centre Hospitalier, Meaux), Dr Pierre-Luc Etienne (Centre Cario-HPCA, Plérin), Dr Sandrine Lavau Denes (Centre Hospitalier Universitaire Dupuytren, Limoges), Pr Thierry Lecomte (Hôpital Trousseau, Tours), Dr Vincent Hautefeuille (Hôpital Nord, Amiens), Pr Romain Coriat (Hôpital Cochin, Paris), Pr David Tougeron (Hôpital de la Milétrie, Poitiers), Dr Mathieu Baconnier (Centre Hospitalier Annecy-Genevois, Pringy), Pr Pierre Michel (Hôpital Charles Nicolle, Rouen), Dr Valérie Blondin (Hôpital Charles Nicolle, Rouen), Dr Olivier Joseph capitain (Institut de Cancérologie de l’Ouest Site Paul Papin, Angers), Dr Anne-Laure Villing (Centre Hospitalier, Auxerre), Dr Olivier Boulat (Hôpital Henri Duffaut, Avignon), Dr Anne-Marie Queuniet (Centre Hospitalier Intercommunal Elbeuf-Louviers-Val de Reuil, Elbeuf), Dr Véronique Jestin Le Tallec (Hôpital Morvan, Brest), Dr Robert Herve (Clinique Clairval, Marseille), Dr Virginie Sebbagh (Centre Hospitalier, Compiègne), Dr Isabelle Baumgaertner (Hôpital Henri Mondor, Créteil), Dr Gilles Boschetti (Hôpital Edouard Herriot, Lyon), Dr Amar Aouakli (Centre Hospitalier de l’Arrondissement de Montreuil, Rang du Fliers), Pr Emmanuel Mitry (Institut Curie, Saint Cloud), Dr Elisabeth carola (Centre Hospitalier, Senlis), Dr Ahmed Bedjaoui (Hôpitaux du Léman, Thonon Les Bains), Dr Hélène castanie (Institut de Cancérologie de l’Ouest – Site René Gauducheau, Saint Herblain), Pr Jean-Yves Douillard (Institut de Cancérologie de l’Ouest – Site René Gauducheau, Saint Herblain), Dr Hélène Senellart (Institut de Cancérologie de l’Ouest – Site René Gauducheau, Saint Herblain), Dr Sandrine Hiret (Institut de Cancérologie de l’Ouest – Site René Gauducheau, Saint Herblain), Dr Véronique Lorgis (Centre Georges François Leclerc, Dijon), Dr Aude Vincent (Centre Georges François Leclerc, Dijon)Pr Michel Ducreux (Institut Gustave Roussy, Villejuif), Dr Pascal Burtin (Institut Gustave Roussy, Villejuif), Dr David Malka (Institut Gustave Roussy, Villejuif), Dr Elie Zrihen (Institut Gustave Roussy, Villejuif), Dr Antoine Hollebecque (Institut Gustave Roussy, Villejuif), Dr Bruno Landi (Hôpital Européen Georges Pompidou, Paris), Dr Isabelle Trouilloud (Hôpital Européen Georges Pompidou, Paris), Dr Philippe Follana (Centre Antoine Lacassagne, Nice), Dr Xavier Coulaud (Centre Hospitalier de Saint Etienne – Hôpital Nord, Saint Priest en Jarez), Dr Christian Borel (Centre Paul Strauss, Strasbourg), Dr Christine Belletier (Centre Paul Strauss, Strasbourg), Dr François Dewaele (Centre Hospitalier Départemental Vendée, La Roche-Sur-Yon), Dr Thierry Chatellier (Centre Hospitalier Départemental Vendée, La Roche-Sur-Yon) ET (Clinique Mutualiste de l’Estuaire, Saint Nazaire), Pr Laétitia Dahan (Centre Hospitalier Universitaire La Timone, Marseille), Dr Muriel duluc (Centre Hospitalier Universitaire La Timone, Marseille), Dr Emmanuelle Norguet monnereau (Centre Hospitalier Universitaire La Timone, Marseille), Dr Catherine Bechi (Centre de Cancérologie du Grand Montpellier), Dr Béatrice Lafforgue (Centre de Cancérologie du Grand Montpellier), Dr Eric Janssen (Centre de Cancérologie du Grand Montpellier), Pr Laurent Bedenne (Centre Hospitalier Universitaire François Mitterrand, Dijon), Pr Côme Lepage (Centre Hospitalier Universitaire François Mitterrand, Dijon), Dr Paul Arthur Haineaux (Centre Hospitalier Universitaire François Mitterrand, Dijon), Dr Franck Audemar (Centre Hospitalier Côte Basque, Bayonne) ET (Centre Hospitalier Saint Jean, Perpignan), Dr Christelle De La Fouchardiere (Centre Léon Bérard, Lyon), Dr Jérôme Dauba (Hôpital Layné, Mont de Marsan), Dr Yves Bechade (Institut Bergonié, Bordeaux), Pr Dominique Bechade (Institut Bergonié, Bordeaux), Dr Laurent Cany (Clinique Francheville, Périgueux), Dr Charles-Briac Levache (Clinique Francheville, Périgueux), Dr Nicolas Barriere (Hôpital Européen, Marseille), Pr Jean-Baptiste Bachet (Hôpital La Pitié Salpetrière, Paris), Dr Touraj Mansourbakht (Hôpital La Pitié Salpetrière, Paris), Dr Lynn Rob (Institut de Cancérologie de Lorraine - Alexis Vautrin, Vandoeuvre Les Nancy), Pr Thierry Conroy (Institut de Cancérologie de Lorraine - Alexis Vautrin, Vandoeuvre Les Nancy), Dr Marie-Christine Kaminsky (Institut de Cancérologie de Lorraine - Alexis Vautrin, Vandoeuvre Les Nancy), Dr Isabelle Cumin (Centre Hospitalier de Bretagne Sud-Hôpital du Scorff, Lorient), Dr Joëlle Egreteau (Centre Hospitalier de Bretagne Sud-Hôpital du Scorff, Lorient), Dr Régine Lamy (Centre Hospitalier de Bretagne Sud-Hôpital du Scorff, Lorient), Dr Jean-Marc Gornet (Hôpital Saint Louis, Paris), Dr Oana Cojocarasu (Centre Hospitalier, Le Mans), Dr Mohamed Gasmi (Centre Hospitalier Universitaire – Hôpital Nord, Marseille), Dr Dominique Luet (Centre Hospitalier Universitaire, Angers), Pr François-Xavier Caroli-Bosc (Centre Hospitalier Universitaire, Angers), Dr Guillaume Roquin (Centre Hospitalier Universitaire, Angers), Dr Caroline Couffon (Centre Hospitalier Universitaire, Angers), Dr Benjamin Linot (Institut de Cancérologie de l’Ouest – Site Paul Papin, Angers), Dr Véronique Guerin-meyer (Institut de Cancérologie de l’Ouest – Site Paul Papin, Angers), Dr Suzanne Nguyen (Centre Hospitalier, Beauvais), Dr Nathalie Gerardin (Centre Hospitalier, Montauban), Dr Miguel Carreiro (Centre Hospitalier, Montauban), Dr Corinne Sarda (Centre Hospitalier Intercommunal Castres-Mazamet, Castres), Dr Nathalie Hess laurens (Centre Hospitalier Intercommunal Castres-Mazamet, Castres), Dr Yann Molin (Hôpital Edouard Herriot, Lyon), Dr Catherine Lombard-bohas (Hôpital Edouard Herriot, Lyon), Pr Thomas Walter (Hôpital Edouard Herriot, Lyon), Dr Julien Forestier (Hôpital Edouard Herriot, Lyon), Dr Hatem Salloum (Centre Hospitalier, Meaux), Dr Farah Zerouala Boussaha (Centre Hospitalier, Meaux), Dr Jérôme Meunier (Centre Hospitalier Départemental Vendée, Orléans), Dr Corina Cornila (Centre Hospitalier Départemental Vendée, Orléans), Dr Laetitia Stefani (Centre Hospitalier Annecy Genevois, Pringy), Dr Christian Maillard (Centre Hospitalier Annecy-Genevois, Pringy), Dr Marc Porneuf (Hôpital Yves Le Foll, Saint Brieuc), Dr Vincent Quentin (Hôpital Yves Le Foll, Saint Brieuc), Dr Claire Giraud (Centre Léonard de Vinci, Dechy), Dr Jean-Marie Vantelon (Centre Léonard de Vinci, Dechy), Dr Anne Cadier Lagnes (Centre Hospitalier Côte Basque, Bayonne), Dr Mohammed Ramdani (Centre Hospitalier, Béziers), Dr Yann Le Bricquir (Centre Hospitalier, Béziers), Dr Florence Kikolski (Hôpital Robert Boulin, Libourne), Dr Gaël Goujon (Hôpital Bichat, Paris), Dr Eric Terrebonne (Hôpital du Haut Lévèque, Pessac), Dr Julien Vergniol (Hôpital du Haut Lévèque, Pessac), Dr Sophie Pesque-Penaud (Hôpital du Haut Lévèque, Pessac), Dr Marie-Claude Gouttebel (Hôpitaux Drôme Nord – Site de Romans, Romans sur Isère), Dr Laurent Gasnault (Centre Joliot Curie, Saint Martin Les Boulogne), Dr Annunziato Alessio (Clinique Trenel, Sainte Colombe les Vienne), Dr Ivan graber (Clinique Trenel, Sainte Colombe les Vienne), Pr Etienne Dorval Danquechin (Hôpital Trousseau, Tours), Dr Dany Gargot (Centre Hospitalier, Blois), Dr Vincent Bourgeois (Hôpital Duchenne, Boulogne sur Mer), Dr Anne-Marie Queuniet (Centre Hospitalier Intercommunal Elbeuf-Louviers-Val de Reuil, Elbeuf), Dr Dominique Sevin Robiche (Polyclinique Sainte Marguerite, Auxerre), Dr Stéfanie Oddou Lagraniere (Hôpital Général, Gap), Dr Joël Ezenfis (Centre Hospitalier, Longjumeau), Dr Denis Pere Verge (Hôpital Saint Joseph Saint Luc, Lyon), Souquet Jean-Christophe (Hôpital de la Croix Rousse, Lyon), Dr Lionel Wander (Hôpital de la Croix Rousse, Lyon), Dr Abakar Abakar Mahamat (Hôpital l’Archet II, Nice), Dr Jacques Cretin (Institut de Cancérologie du Gard, Nîmes), Dr Anne-Claire Dupont gossart (Hôpital Jean Minjoz, Besançon), Dr Philippe Martin (Centre Hospitalier Intercommunal, Créteil), Dr Geneviève Boilleau-Jolimoy (Institut de cancérologie de Bourgogne – GRReCC, Dijon), Dr Anne Thirot Bidault (Hôpital de Bicêtre, Kremlin-Bicêtre), Dr Ahmed Azzedine (Centre Hospitalier, Montélimar),Dr Zied Ladhib (Centre Hospitalier, Valence).

    • Correction notice This article has been corrected since it published Online First. The author Thomas Aparicio’s name has been corrected.

    • Patient consent for publication Not required.

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