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

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