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Marc E. Buyse

Marc E. Buyse. Endpoints in adjuvant trials: a systematic review of the literature in colon cancer and proposed definitions for future trials. Collaborators. Buyse M, Punt CJA, Köhne CH, Hohenberger P, Labianca R, Schmoll HJ, Pahlman L, Sobrero A, and Douillard JY

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Marc E. Buyse

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  1. Marc E. Buyse Endpoints in adjuvant trials: a systematic review of the literature in colon cancer and proposed definitions for future trials

  2. Collaborators Buyse M,Punt CJA, Köhne CH, Hohenberger P, Labianca R, Schmoll HJ, Pahlman L, Sobrero A, and Douillard JY International Drug Development Institute, Louvain-la-Neuve, Belgium; Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands;Klinikum Oldenburg, Germany; Medical Faculty Mannheim and University of Heidelberg,Germany; Ospedale Riuniti, Bergamo, Italy; University Hospital, Uppsala, Sweden; Ospedale S. Martino, Genova, Italy; and Centre René Gauducheau, Nantes Saint-Herblain, France

  3. Background • Disease-free survival is increasingly used as the primary endpoint in trials of adjuvant treatments for colorectal cancer • Published papers use different endpoints such as relapse-free survival, time to recurrence, etc. • There are no uniform definitions for these endpoints

  4. Importance of endpoint definition (1) In INT0035, the time to recurrence curve flattened after 5 years (Moertel et al, Ann Intern Med 1995)

  5. Importance of endpoint definition (2) In INT0089, the disease-free survival curve continued to decline (Haller et al, JCO 2005)

  6. RFS - Stage III 1.0 0.9 0.8 0.7 IF Probability F 0.6 0.5 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Duration (months) Importance of endpoint definition (3) In PETACC-3, relapse-free survival showed a significant benefit of irinotecan (Van Cutsem et al, ASCO 2005) HR = 0.86, P = .045

  7. DFS - Stage III 1.0 0.9 0.8 IF 0.7 F Probability 0.6 0.5 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Duration (months) Importance of endpoint definition (4) In PETACC-3, disease-free survival failed to detect a significant benefit of irinotecan (Van Cutsem et al, ASCO 2005) HR = 0.89, P = .09

  8. Systematic literature review • All papers with results of phase III clinical trials of adjuvant treatments for colon cancer published in the peer-reviewed English language literature in the period 1997-2006 • Definitions for various endpoints extracted from papers

  9. Results • 52 trials identified • 19 (37%) trials did not define primary endpoint • 17 (33%) trials used DFS without exact definition • 30 (58%) trials did not specify start date for primary endpoint

  10. Endpoints used in published trials • Disease-free survival (DFS) • Disease-free interval (DFI) • Relapse-free survival (RFS) • Relapse-free interval (RFI) • Time to recurrence (TTR) • Disease-specific survival (DSS) • Event-free survival (EFS) • Recurrence rate (RR)

  11. Number of trials using various endpoints Some trials used multiple endpoints

  12. Endpoint definitions • A consensus was sought for the definition of each endpoint • Key features of each endpoint are: • Start date • Events considered as failures (end date) • Events considered as censored observations • Events ignored

  13. Endpoint definitions • Disease-free survival (DFS): time to any event • Relapse-free survival (RFS): time to any event except second primary cancers • Time to recurrence (TTR): time to any event related to primary colorectal cancer • Time to treatment failure (TTF): time to any event except non-cancer deaths • Cancer-specific survival (CSS): time to death from colorectal cancer • Overall survival (OS): time to any death

  14. Failures and censored observations  = failure = censored observation

  15. Requirements for ideal endpoint Ideal endpoint should • capture all clinically relevant events • have unbiased start and end dates • have little opportunity for ascertainment bias • be observed as early as possible • be observed in as many patients as possible • be statistically sensitive to real treatment benefits

  16. Tentative recommendations • DFS fulfils most requirements of ideal endpoint • TTR may be more sensitive to real treatment benefits • Start date should be date of randomization • OS should always remain secondary endpoint

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