title: Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial.
abstract: BACKGROUND
  The effect of imatinib discontinuation on progression-free survival and overall survival in long-lasting responders with advanced gastrointestinal stromal tumours (GIST) is unknown. We assessed treatment interruption in patients with non-progressive disease according to the Response Evaluation Criteria In Solid Tumors criteria after 3 years of imatinib in a randomised trial.
  
  
  METHODS
  In this open-label national multicentre phase 3 study in France, patients with GIST free of progression after 3 years of imatinib 400 mg/day were randomly assigned to continue or interrupt imatinib. Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of two and four patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. An interim analysis was planned after the first 50 randomly assigned patients. Analysis was done according to the intention-to-treat principle-ie, all patients randomly assigned to a study group were included. This study is registered with ClinicalTrial.gov, number NCT00367861.
  
  
  RESULTS
  434 patients were enrolled in this trial between May 27, 2002, and May 5, 2009. Between June 13, 2005, and May 30, 2007, 50 patients with non-progressive disease who had received 3 years of treatment with imatinib were randomly assigned to continue or interrupt their treatment, 25 patients in each group. By Dec 7, 2009, after a median follow-up of 35 months (95% CI 33-38) after random assignment, 2-year progression-free survival was 80% (95% CI 58-91) in the continuation group and 16% (5-33) in the interruption group (p < 0·0001). There was no difference in adverse events grade 3 or greater (oedema and asthenia) between the two groups.
  
  
  CONCLUSIONS
  Imatinib interruption after 3 years in responders results in a high risk of rapid progression in patients with advanced GIST. Discontinuation of imatinib is not recommended outside clinical trials unless patients experience significant toxic effects.
  
  
  BACKGROUND
  Conticanet, the Ligue Contre Le Cancer du Rhone, and Novartis.
authors.affiliation: Institut Gustave Roussy, Villejuif, France. lecesne@igr.fr
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Binh Nguyen
authors.initials: BN
authors.lastname: Bui
authors.forename: Antoine
authors.initials: A
authors.lastname: Adenis
authors.forename: Maria
authors.initials: M
authors.lastname: Rios
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Florence
authors.initials: F
authors.lastname: Duffaud
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.forename: Didier
authors.initials: D
authors.lastname: Cupissol
authors.forename: Angela
authors.initials: A
authors.lastname: Cioffi
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chabaud
authors.forename: David
authors.initials: D
authors.lastname: Pérol
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005602:France; D005770:Gastrointestinal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate