title: Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting.
abstract: BACKGROUND
  Imatinib 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.
  
  
  METHODS
  Advanced 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.
  
  
  RESULTS
  Small 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.
  
  
  CONCLUSIONS
  Concentration 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.
authors: Univ. de Bordeaux, Bordeaux, F-33000, France; INSERM, U1219, Bordeaux, F-33000, France; CHU de Bordeaux, Bordeaux, F-33000, France.
authors: Stéphane
authors: S
authors: Bouchet
authors: Univ. de Bordeaux, Bordeaux, F-33000, France.
authors: Sylvie
authors: S
authors: Poulette
authors: Univ. de Bordeaux, Bordeaux, F-33000, France; INSERM, U1219, Bordeaux, F-33000, France; CHU de Bordeaux, Bordeaux, F-33000, France.
authors: Karine
authors: K
authors: Titier
authors: Univ. de Bordeaux, Bordeaux, F-33000, France; INSERM, U1219, Bordeaux, F-33000, France; CHU de Bordeaux, Bordeaux, F-33000, France.
authors: Nicholas
authors: N
authors: Moore
authors: Univ. de Bordeaux, Bordeaux, F-33000, France; INSERM CIC Bordeaux CIC1401 Pharmaco-épidemiologie, Bordeaux, F-33000, France.
authors: Régis
authors: R
authors: Lassalle
authors: Univ. de Bordeaux, Bordeaux, F-33000, France; INSERM CIC Bordeaux CIC1401 Pharmaco-épidemiologie, Bordeaux, F-33000, France.
authors: Abdelilah
authors: A
authors: Abouelfath
authors: Institut Bergonié, Bordeaux, F-33000, France.
authors: Antoine
authors: A
authors: Italiano
authors: Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, F-31300, France.
authors: Christine
authors: C
authors: Chevreau
authors: Centre René Gauducheau, Nantes (Saint-Herblain), F-44805, France.
authors: Emmanuelle
authors: E
authors: Bompas
authors: Institut de Cancérologie Lucien Neuwirth, Saint Priest-en-Jarez, F-42270, France.
authors: Olivier
authors: O
authors: Collard
authors: CHU La Timone, Marseille, F-13385, France; Aix Marseille Université (AMU), France.
authors: Florence
authors: F
authors: Duffaud
authors: Institut de Cancérologie de Lorraine - Alexis Vautrin, Nancy, F-54500, France.
authors: Maria
authors: M
authors: Rios
authors: Centre Val d'Aurelle, Montpellier, F-34298, France.
authors: Didier
authors: D
authors: Cupissol
authors: Centre Oscar Lambret, Lille, F-59020, France.
authors: Antoine
authors: A
authors: Adenis
authors: Centre Léon Bérard, Lyon, F-69008, France; Université Claude Bernard Lyon 1, France.
authors: Isabelle
authors: I
authors: Ray-Coquard
authors: CHU Robert Debré, Reims, F-51092, France.
authors: Olivier
authors: O
authors: Bouché
authors: Institut Gustave-Roussy, Villejuif, F-94805, France.
authors: Axel
authors: A
authors: Le Cesne
authors: Institut Bergonié, Bordeaux, F-33000, France.
authors: Binh
authors: B
authors: Bui
authors: Centre Léon Bérard, Lyon, F-69008, France; Université Claude Bernard Lyon 1, France.
authors: Jean-Yves
authors: JY
authors: Blay
authors: Univ. de Bordeaux, Bordeaux, F-33000, France; INSERM, U1219, Bordeaux, F-33000, France; CHU de Bordeaux, Bordeaux, F-33000, France. Electronic address: mathieu.molimard@u-bordeaux.fr.
authors: Mathieu
authors: M
authors: Molimard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D018450:Disease Progression; D016903:Drug Monitoring; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D046152:Gastrointestinal Stromal Tumors / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate / Q000378:metabolism / Q000493:pharmacokinetics*; D007421:Intestine, Small / Q000737:chemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013270:Stomach / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate
keywords: Gastrointestinal stromal tumour; Imatinib; Therapeutic drug monitoring