title: Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, Alone and in Sequence.
abstract: To investigate adherence to endocrine treatment and its relationship with disease-free survival (DFS) in the Breast International Group (BIG) 1-98 clinical trial.
  
  
  
  The BIG 1-98 trial is a double-blind trial that randomly assigned 6,193 postmenopausal women with hormone receptor-positive early breast cancer in the four-arm option to 5 years of tamoxifen (Tam), letrozole (Let), or the agents in sequence (Let-Tam, Tam-Let). This analysis included 6,144 women who received at least one dose of study treatment. Conditional landmark analyses and marginal structural Cox proportional hazards models were used to evaluate the relationship between DFS and treatment adherence (persistence [duration] and compliance with dosage). Competing risks regression was used to assess demographic, disease, and treatment characteristics of the women who stopped treatment early because of adverse events.
  
  
  
  Both aspects of low adherence (early cessation of letrozole and a compliance score of < 90%) were associated with reduced DFS (multivariable model hazard ratio, 1.45; 95% CI, 1.09 to 1.93; P = .01; and multivariable model hazard ratio, 1.61; 95% CI, 1.08 to 2.38; P = .02, respectively). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age, smoking, node negativity, or prior thromboembolic event.
  
  
  
  Both persistence and compliance are associated with DFS. Toxicity management and, for sequential treatments, patient and physician awareness, may improve adherence.
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary. chirgwin@tpg.com.au.
authors.forename: Jacquie H
authors.initials: JH
authors.lastname: Chirgwin
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Giobbie-Hurder
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Coates
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Price
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Marc
authors.initials: M
authors.lastname: Debled
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Manuela
authors.initials: M
authors.lastname: Rabaglio
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: John F
authors.initials: JF
authors.lastname: Forbes
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Láng
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Marco
authors.initials: M
authors.lastname: Colleoni
authors.affiliation: Jacquie H. Chirgwin and John F. Forbes, University of Newcastle; John F. Forbes, Calvary Mater Newcastle, Newcastle; Alan S. Coates, University of Sydney School of Public Health, Sydney, New South Wales; Jacquie H. Chirgwin, Box Hill Hospital; Jacquie H. Chirgwin, Maroondah Hospital; Jacquie H. Chirgwin, Monash University, Melbourne, Victoria, Australia; Anita Giobbie-Hurder, Karen N. Price, and Richard D. Gelber, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard Medical School, Boston, MA; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Marc Debled, Institut Bergonié, Bordeaux, France; Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy; Ian Smith, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Manuela Rabaglio, Inselspital, Bern; Beat Thürlimann, Kantonsspital, St. Gallen, Switzerland; Patrick Neven, University of Leuven; Patrick Neven, University Hospitals Leuven, Leuven, Belgium; István Láng, National Institute of Oncology, Budapest, Hungary.
authors.forename: Beat
authors.initials: B
authors.lastname: Thürlimann
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000077289:Letrozole; D055118:Medication Adherence; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D013629:Tamoxifen / Q000008:administration & dosage / Q000627:therapeutic use*; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole