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

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 Duration (months) Probabili ty IF F 0.0 0.5 0.6 0.7 0.8 0.9 1.0 036912151821242730333639424548 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. IF F 0.0 Probabilit y 0.5 0.6 0.7 0.8 0.9 1.0 Duration (months) 036912151821242730333639424548 DFS - Stage III 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 Endpoint Events considered as failures: DFSDFIRFSRFITTRDSSEFSRR Recurrence, second primary cancer or death 131 Recurrence or death1011 Recurrence4221 Recurrence, second primary colon cancer, death due to toxicity or to colon cancer 1 Recurrence of any malignancy1 Deaths from cancer1 Not specified1711 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 Endpoint EventDFSRFSTTRTTFCSSOS Locoregional recurrence  Distant metastases  Second primary, same cancer  Second primary, other cancer  Death from same cancer  Death from other cancer  Non-cancer death  Treatment-related death  Loss to follow- up   = 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