Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting |
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| Institution: | 1. Univ. de Bordeaux, Bordeaux, F-33000, France;2. INSERM, U1219, Bordeaux, F-33000, France;3. CHU de Bordeaux, Bordeaux, F-33000, France;4. INSERM CIC Bordeaux CIC1401 Pharmaco-épidemiologie, Bordeaux, F-33000, France;5. Institut Bergonié, Bordeaux, F-33000, France;6. Institut Universitaire du Cancer Toulouse – Oncopole, Toulouse, F-31300, France;7. Centre René Gauducheau, Nantes (Saint-Herblain), F-44805, France;8. Institut de Cancérologie Lucien Neuwirth, Saint Priest-en-Jarez, F-42270, France;9. CHU La Timone, Marseille, F-13385, France;10. Aix Marseille Université (AMU), France;11. Institut de Cancérologie de Lorraine – Alexis Vautrin, Nancy, F-54500, France;12. Centre Val d''Aurelle, Montpellier, F-34298, France;13. Centre Oscar Lambret, Lille, F-59020, France;14. Centre Léon Bérard, Lyon, F-69008, France;15. Université Claude Bernard Lyon 1, France;p. CHU Robert Debré, Reims, F-51092, France;q. Institut Gustave-Roussy, Villejuif, F-94805, France;1. Medical Student, Department of Oral and Maxillofacial Surgery, Oxford University Medical School, Oxford, Oxfordshire, UK;2. Senior House Officer, Department of Oral and MaxilloFacial Surgery, Oxford University Hospitals National Health Service Foundation Trust, Oxford, Oxfordshire, UK;3. Consultant, Department of Radiology, Oxford University Hospitals National Health Service Foundation Trust, Oxford, Oxfordshire, UK;4. Consultant, Department of Oral and Maxillo-Facial Surgery, Oxford University Hospitals National Health Service Foundation Trust, Oxford, Oxfordshire, UK;1. Department of Medical Oncology, Henri Mondor Hospital, APHP, Creteil, France;2. Memorial Sloan Kettering Cancer Center, New York, USA;3. Pharmacology Unit, Henri Mondor Hospital, APHP, Creteil, France;4. GERCOR, Paris, France;5. Methodology and Quality of Life Unit, Department of Medical Oncology, University Hospital, Besançon, France;6. Bourgogne Franche-Comté University, INSERM, Etablissement Français Du Sang Bourgogne Franche-Comté, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, UMR1098, Besançon, France;7. Sorbonne University and Department of Medical Oncology, Saint-Antoine Hospital, Paris, France;8. Sorbonne University and Radiology Unit, Pitié-Salpétrière Hospital, APHP, Paris, France;9. Department of Medical Oncology, Besancon University Hospital, Besancon, France;10. Sorbonne University and Pitié-Salpêtrière Hospital, Paris, France;11. Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Université de Montpellier, Institut Régional Du Cancer de Montpellier, Montpellier, France;12. Institut Mutualiste Montsouris, Paris, France;13. Medical Oncology, Institut Hospitalier Franco-Britannique-Levallois-Perret, France;1. Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai 400012, India;2. Department of Haematology, 10th Floor, New Multistoried Building, KEM Hospital, Parel, Mumbai 400012, India;1. Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India;2. Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India;3. Department of Pediatrics (Genetics Unit), All India Institute of Medical Sciences, New Delhi 110029, India;1. Department of Oncological Medicine, Gustave Roussy, Villejuif, France;2. Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France;3. Medical School, University of Paris XI Sacly, Saclay, France;4. Department of Therapeutic Innovations and Early Trials, Gustave Roussy, Villejuif, France;5. Medical Oncology Hopital Europeen Georges Pompidou, Paris, France;6. Department of Biostatistics and Epidemiology, Gustave Roussy, Paris, France;7. Functional Unity (UF) Drug Biology and Toxicology Department, Hopital Cochin, Paris, France;8. UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, University of Paris, Paris, France;1. Oncology Unit, University Hospital, Parma, Italy;2. Department of Clinical and Experimental Medicine, University Hospital, Parma, Italy;3. INAIL Research Area, CERT, University of Parma, Parma, Italy;4. Section of Pathological Anatomy, University Hospital, Parma, Italy;5. Department of Experimental and Applied Medicine, Section of Occupational Health and Industrial Hygiene, University of Brescia, Brescia, Italy |
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| Abstract: | BackgroundImatinib has dramatically improved the prognosis of advanced gastrointestinal stromal tumours (GISTs). Clinical trial data showed that patients with trough imatinib plasma concentrations (Cmin) below 1100 ng/ml (quartile 1) had shorter time to progression, but no threshold has been defined.The main objective of this study was to investigate in advanced GIST whether a Cmin threshold value associated with a longer progression-free survival (PFS) could be specified. This would be the first step leading to therapeutic drug monitoring of imatinib in GIST.Patients and methodsAdvanced GIST patients (n = 96) treated with imatinib 400 mg/d (41 stomach, 34 small bowel, and 21 other primary site localisations) were prospectively included in this real-life setting study. Routine plasma level testing imatinib (Cmin) and clinical data of were recorded prospectively.ResultsSmall bowel localisation was associated with an increased relative risk of progression of 3.09 versus stomach localisation (p = 0.0255). Mean Cmin (±standard deviation) was 868 (±536) ng/ml with 75% inter-individual and 26% intra-patient variability. A Cmin threshold of 760 ng/ml defined by log-rank test was associated with longer PFS for the whole population (p = 0.0256) and for both stomach (p = 0.043) and small bowel (p = 0.049) localisations when analysed separately. Multivariate Cox regression analysis found that Cmin above 760 ng/ml was associated with 65% reduction risk of progression (p = 0.0271) in the whole population independently of the anatomical localisation.ConclusionConcentration of imatinib significantly influences duration of tumour control treatment in GIST patients with a Cmin threshold of 760 ng/ml associated with prolonged PFS in real-life setting. |
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| Keywords: | Imatinib Gastrointestinal stromal tumour Therapeutic drug monitoring |
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