marc e. buyse
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
Endpoints in adjuvant trials: a systematic review of the
literature in colon cancer and proposed definitions for future
trials
Marc E. Buyse
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
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
Importance of endpoint definition (1)
In INT0035,the time to recurrencecurve flattenedafter 5 years(Moertel et al,Ann InternMed 1995)
Importance of endpoint definition (2)
In INT0089,the disease-free survivalcurve continuedto decline(Haller et al,JCO 2005)
RFS - Stage III
Duration (months)
Pro
bab
ility
IF
F
0.0
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Importance of endpoint definition (3)
In PETACC-3,relapse-freesurvivalshowed a significant benefit of irinotecan(Van Cutsem et al, ASCO 2005)
HR = 0.86, P = .045
IF
F
0.0
Pro
bab
ilit
y
0.5
0.6
0.7
0.8
0.9
1.0
Duration (months)0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
DFS - Stage III
Importance of endpoint definition (4)
In PETACC-3,disease-freesurvivalfailed to detect asignificant benefit of irinotecan(Van Cutsem et al, ASCO 2005)
HR = 0.89, P = .09
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
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
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)
Number of trials using various endpointsEndpoint
Events considered as failures:
DFS
DFI
RFS
RFI TTR
DSS
EFS
RR
Recurrence, second primary cancer or death
13 1
Recurrence or death 10 1 1
Recurrence 4 2 2 1
Recurrence, second primary colon cancer, death due to toxicity or to colon cancer
1
Recurrence of any malignancy
1
Deaths from cancer 1
Not specified 17 1 1Some trials used multiple endpoints
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
Endpoint definitions
Disease-free survival (DFS): time to any eventRelapse-free survival (RFS): time to any event except second primary cancersTime to recurrence (TTR): time to any event related to primary colorectal cancerTime to treatment failure (TTF): time to any event except non-cancer deathsCancer-specific survival (CSS): time to death from colorectal cancerOverall survival (OS): time to any death
Failures and censored observationsEndpoint
Event DFS RFS TTR TTF CSS
OS
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
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