title: Crizotinib Associated with Ground-Glass Opacity Predominant Pattern Interstitial Lung Disease: A Retrospective Observational Cohort Study with a Systematic Literature Review.
abstract: BACKGROUND
  Crizotinib, an oral tyrosine kinase inhibitor that targets anaplastic lymphoma kinase, has proven to offer sustained progression-free survival in anaplastic lymphoma kinase-rearranged non-small-cell lung cancers. Occurrence of severe interstitial lung disease (ILD) was one of the crucial adverse events reported in randomized clinical trials and case reports.
  
  
  METHODS
  In September 2011, we observed a crizotinib-associated ILD case. Following this index case, we reviewed the clinical and computed tomographic scan features of all patients treated with crizotinib in our department, between October 2010 and July 2013, comparing patients with and without ILD. A systematic literature review was performed.
  
  
  RESULTS
  During this period, 29 patients were treated with crizotinib, five of whom developed ILD, in addition to the index case. Two types of adverse lung reactions may be observed in patients undergoing crizotinib therapy. The first is a severe, usually fatal, ILD that occurs during the first month of treatment (n = 1). The second is a less severe ILD, occurring later in time (n = 5). It occurs gradually with only few clinical symptoms, but predominant ground-glass opacities on computed tomography, along with an intensive lymphocytic alveolitis in bronchoalveolar lavage fluid. These cases had a longer response with a median progression-free survival duration at 19.9 months (17.9-23.5) compared with 6.2 months (1.2-13.6) for controls (p = 0.04).
  
  
  CONCLUSIONS
  Forty-nine cases of crizotinib-associated ILD have been identified by the systematic review of the literature, including our six cases. Two types of adverse lung reactions may be observed with different presentation, prognosis, and treatment. Their potential mechanisms should be clarified. Nine patients with the less severe form of ILD were safely retreated.
authors.affiliation: *Service de Pneumologie, AP-HP, Hôpital Tenon, Paris, France; †Sorbonne Universités, UPMC Univ Paris 06, Theranoscan, Paris, France; ‡Service d'Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Tenon, Paris, France; §Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil, France; ‖Service de Pneumologie, Hôpital Foch, Suresnes, France; ¶Service de Pharmacie, AP-HP, Hôpital Tenon, Paris, France; and #Service d'Anatomie Pathologique, AP-HP, Hôpital Tenon, Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Créquit
authors.forename: Marie
authors.initials: M
authors.lastname: Wislez
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Fleury Feith
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rozensztajn
authors.forename: Laurence
authors.initials: L
authors.lastname: Jabot
authors.forename: Sylvie
authors.initials: S
authors.lastname: Friard
authors.forename: Armelle
authors.initials: A
authors.lastname: Lavole
authors.forename: Valérie
authors.initials: V
authors.lastname: Gounant
authors.forename: Julie
authors.initials: J
authors.lastname: Fillon
authors.forename: Martine
authors.initials: M
authors.lastname: Antoine
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D000077547:Crizotinib; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000139:chemically induced* / Q000000981:diagnostic imaging; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011720:Pyrazoles / Q000009:adverse effects*; D011725:Pyridines / Q000009:adverse effects*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015996:Survival Rate; D014057:Tomography, X-Ray Computed
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases