Disease-free survival is increasingly being used as the primary endpoint of most trials testing adjuvant treatments in cancer. Other frequently used endpoints include overall survival, recurrence-free survival, and time to recurrence. These endpoints are often defined differently in different trials in the same type of cancer, leading to a lack of comparability among trials. In this Commentary, we used adjuvant studies in colon cancer as a model to address this issue. In a systematic review of the literature, we identified 52 studies of adjuvant treatment in colon cancer published in 1997-2006 that used eight other endpoints in addition to overall survival. Both the definition of these endpoints and the starting point for measuring time to the events that constituted these endpoints varied widely. A panel of experts on clinical research on colorectal cancer then reached consensus on the definition of each endpoint. Disease-free survival--defined as the time from randomization to any event, irrespective of cause--was considered to be the most informative endpoint for assessing the effect of treatment and therefore the most relevant to clinical practice. The proposed guidelines may add to the quality and cross-comparability of future studies of adjuvant treatments for cancer. [References: 59]
AimA consensus process was used to identify the most appropriate starting point for each endpoint, the events that should be taken into account for each endpoint, and which of the endpoints are the most relevant for studies of adjuvant treatment for cancer.
ContributorsPunt, Cornelis J. A. Buyse, Marc Kohne, Claus-Henning Hohenberger, Peter Labianca, Roberto Schmoll, Hans J. Pahlman, Lars Sobrero, Alberto Douillard, Jean-Yves
Disease Category: Cancer
Disease Name: Colorectal cancer
Age Range: Unknown
Sex: Either
Nature of Intervention: Not specified
- Systematic review of outcomes measured in trials
- Definition
- COS for clinical trials or clinical research
- Consensus meeting
- Systematic review
An electronic database search of the peer-reviewed literature was performed to identify phase III clinical trials of adjuvant treatments for colon cancer published from 1997 through 2006. Apart from overall survival, eight additional endpoints were used: disease-free survival (n = 44), disease-free interval (n = 2), relapse-free survival (n = 4), relapse-free interval (n = 1), time to recurrence (n = 3), disease-specifi c survival (n = 1), event-free survival (n = 1), and recurrence rate (n = 1) ( Table 1 ). Some studies used multiple endpoints, and many of these endpoints were defined in multiple ways across studies.
A consensus process was used to identify the most appropriate starting point for each endpoint, the events that should be taken into account for each endpoint, and which of the endpoints are the most relevant for studies of adjuvant treatment for cancer. The consensus panel took as its starting point a proposal for definitions that was made by two authors (C. J. A. Punt, M. Buyse). In evaluating the events that constituted the different endpoints, the consensus panel evaluated whether the nature of the event could be ascertained without bias, whether the date of the event could be ascertained without bias, and whether the event was commonly or rarely observed in patients with primary resectable colon cancer. In evaluating each endpoint, the panel evaluated whether the endpoint had been frequently used in clinical trials so far, the endpoint could be defined unambiguously and in an unbiased fashion in all future trials, and the endpoint would be likely to detect treatment benefits of adjuvant therapies for colon cancer. The panel identified nine events as relevant to the definition of endpoints: locoregional recurrence, distant metastases, second primary colorectal cancer, second primary cancer other than colorectal cancer, death from colorectal cancer, death from other cancer, noncancer death, treatment-related death, and loss to follow- up. Six endpoints were identifi ed as relevant to determine the effect of adjuvant treatment: disease-free survival, time to recurrence, time to treatment failure, relapse-free survival, cancerspecific survival, and overall survival. The panel then reached consensus on the appropriate contribution of the nine events to the definitions of each of the six endpoints and definitions of the six endpoints. After considering all six endpoints, the panel selected diseasefree survival as the most appropriate primary endpoint for future trials of adjuvant treatment for colon cancer or for any type of cancer.