Journal of the National Cancer Institute Advance Access originally published online on June 27, 2007
JNCI Journal of the National Cancer Institute 2007 99(13):998-1003; doi:10.1093/jnci/djm024
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COMMENTARY |
Endpoints in Adjuvant Treatment Trials: A Systematic Review of the Literature in Colon Cancer and Proposed Definitions for Future Trials
Affiliations of authors: Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands (CJAP); International Drug Development Institute, Louvain-la-Neuve, Belgium (MB); Clinic for Oncology and Hematology, Oldenburg Clinic, Oldenburg, Germany (CHK); Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Germany (PH); Unit of Medical Oncology, Riuniti Hospital, Bergamo, Italy (RL); Department of Hematology and Oncology, Martin Luther University, Halle, Germany (HJS); Department of Surgery, University Hospital, SE 751 85 Uppsala, Sweden (LP); Department of Medical Oncology, S. Martino Hospital, Genova, Italy (AS); Center R. Gauducheau 44805 Nantes-St Herblain, France (JYD)
Correspondence to: Cornelis J. A. Punt, MD, PhD, Department of Medical Oncology Radboud University Nijmegen Medical Center, PO Box 9101 6500 HB Nijmegen, The Netherlands (e-mail: c.punt{at}onco.umcn.nl).
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ABSTRACT |
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 Top Abstract Systematic review of the...Consensus on endpoints and...FundingReferencesNotes |
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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.
Overall survival has long been the gold standard primary endpoint for trials of adjuvant treatments for cancer. However, with the increasing number of effective salvage treatments available in many types of cancer, much longer follow-up is required to demonstrate that adjuvant treatments improve overall survival compared with other clinical endpoints. The results of the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study (1) and National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 study (2), both of which showed a benefit in disease-free survival but not (yet) a difference in overall survival, are good examples of this phenomenon and support the need for endpoints that could potentially be used as surrogates for overall survival but can be assessed earlier. In addition, the variable use of salvage treatments among centers or countries may have uncontrollable effects on overall survival benefits. Therefore, surrogate endpoints are needed that allow a better evaluation of the effect of adjuvant treatments.
A recent meta-analysis demonstrated a good correlation between disease-free survival and overall survival of patients treated with adjuvant 5-fluorouracil (5FU)–based chemotherapy after surgical resection of colon cancer (3). Moreover, the effects of 5FU treatment on disease-free survival were predictive of the effects of this treatment on overall survival. Based on these findings, disease-free survival is currently considered to be an acceptable primary endpoint for trials testing adjuvant treatments for colon cancer. However, data from adjuvant studies that use clinical surrogates for overall survival are often difficult to interpret for two reasons. First, surrogate endpoints other than disease-free survival, such as relapse-free survival and time to recurrence, are sometimes used, even when it is not known whether these outcomes are true surrogates for overall survival. Second, different definitions are sometimes used for the same endpoint. For example, many studies consider a second primary tumor as an event without clarifying whether second primary tumors include only second primary tumors of the same cancer as the primary tumor or whether they include any unrelated malignant tumor. Moreover, many publications of adjuvant studies do not define the surrogate clinical endpoint at all. Finally, the starting point from which the time to the event is calculated differs among studies.
The importance of both the choice and the definition of the primary clinical endpoint is demonstrated by the Pan-European Trials in Adjuvant Colon Cancer 3 (PETACC-3) study (4), which showed a statistically significant benefit of adjuvant chemotherapy in stage III colon cancer patients for the secondary endpoint, relapse-free survival, but not for the primary endpoint, disease-free survival. Another example concerns the study by Moertel et al. (5) of 5FU plus levamisole in patients with stage III colon cancer. In this study, the recurrence-free interval curve flattened out after 7–8 years of follow-up; by contrast, the disease-free survival curve of the Intergroup 0089 study (6), in which the same regimen was used, continued to decline even up to 14 years of follow-up. This striking long-term difference may be explained by the fact that second primary cancers and intercurrent deaths (i.e., those occurring before a recurrence of tumor) were not considered to be events in the former study but were in the latter study. The PETACC-3 study (4) and the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) study (7), which were both performed in stage III colon cancer patients, highlight the inconsistencies in the definition of endpoints. Both studies used disease-free survival as primary endpoint, but a second primary cancer other than colon cancer was considered to be an event in the PETACC-3 study and not in the X-ACT study.
Such variations in which endpoints are used and in how they are defined makes it difficult to compare results among studies (8,9) and highlight the need for more uniform definitions and use of endpoints across adjuvant studies in cancer. To try to determine the extent to which these issues could affect trials in colon cancer, we performed a systematic review of the definitions used in published studies over the last decade. We also constituted an international panel of medical oncologists (C. J. A. Punt, C. H. Köhne, R. Labianca, H. J. Schmoll, A. Sobrero, J. Y. Douillard), surgical oncologists (P. Hohenberger, L. Påhlman), and a statistician (M. Buyse), all with expertise in the conduct of studies on colorectal cancer, to reach consensus on the definition of these endpoints as well as on the most relevant endpoint for adjuvant studies.
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Systematic Review of the Literature |
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TopAbstractSystematic review of the...Consensus on endpoints and...FundingReferencesNotes |
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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 (10). Meta-analyses, pooled analyses, retrospective analyses, population-based cohort studies, nonrandomized studies, randomized phase II studies, studies with only overall survival as endpoint, studies in rectal cancer only, and publications not in the English language were excluded. A total of 52 studies were identified that met the criteria for the systematic review (1,6,7,11–59). From each study, one author (C. J. A. Punt) obtained the definition used for each endpoint (if provided). The results of the search were submitted to the other authors of this Commentary for review. The 10-year publication period was chosen arbitrarily, with the assumption that studies published during this period would provide sufficiently representative data for the purpose of this project.
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-specific 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. Three different definitions of disease-free survival were used: time to recurrence, second primary cancer, or death (n = 13); time to recurrence or death (n = 10); and time to recurrence (n = 4). In 17 studies, disease-free survival was used without being defined. Disease-free interval was defined as time to recurrence (n = 2). Relapse-free survival was defined as time to recurrence (n = 2); time to recurrence or death (n = 1); and time to recurrence, second primary colon cancer, death due to treatment-related toxicity, or death due to colon cancer (n = 1). Relapse-free interval was defined as time to recurrence of any malignancy (n = 1). Time to recurrence was defined as time to recurrence (n = 1) and time to recurrence or death (n = 1) or was not defined (n = 1). For disease-specific survival, deaths not related to disease were censored (n = 1). Event-free survival was defined as the time to recurrence, second primary cancer, or death (n = 1). Recurrence rate was used without being defined in one study. When a second primary tumor was included in the definition of an endpoint, only rarely was it specified whether this tumor had to be a second colorectal cancer or whether it could be any type of cancer. In only one study was a recurrence of another cancer explicitly included in the definition of an endpoint that included a second primary tumor. Nineteen studies (37%) provided no definition of the endpoint used.
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The studies also differed in how the time to event was calculated. For 13 studies (25%), the starting time was the date of randomization, and for nine studies (17%), it was the date of surgery. The starting point was not specified in the remaining 30 studies (58%).
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Consensus on Endpoints and Definitions |
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TopAbstractSystematic review of the...Consensus on endpoints and...FundingReferencesNotes |
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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 identified as relevant to determine the effect of adjuvant treatment: disease-free survival, time to recurrence, time to treatment failure, relapse-free survival, cancer-specific 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. For one event, second primary cancers, three topics were addressed. First, the panel agreed that second primary colorectal cancers are distinct from recurrence/relapses because the effect of adjuvant treatment on residual cancer cells (which, when unsuccessful, results in relapse) should be separated from its effect on the development of a new primary tumor, especially when adjuvant treatment has been completed. Second, the panel agreed that a second other primary cancer might be caused by the study treatment itself, but such a cancer cannot be distinguished from a random event. Therefore, second primary cancers were defined in a way that allowed for either possibility. Third, the panel agreed that other diseases (e.g., diabetes mellitus) might also be caused by the study treatment itself. Although it could be argued that such diseases are as important in evaluating treatment effect as a second other cancer, the panel concluded that, because of the likelihood that documentation of diabetes and other noncancer diagnoses would differ substantially among trials and even among institutions within a single trial, such diagnoses should generally not be taken into account in defining endpoints but should be reported as part of the safety analyses of the trial.
The panel also recommended that the causes for non–cancer-related deaths should be presented in the study results, to the extent possible and with due acknowledgment to the limitations of such data. For survival endpoints, all deaths should be considered events. It was als agreed that censoring should be uninformative (i.e., unrelated to treatment) and kept to a minimum (so that any arbitrary censoring of the observations, for instance in case of a treatment change, should be avoided).
The consensus panel developed the following definitions of the six endpoints, which were also considered to be appropriate irrespective to the type of cancer studied (Table 2).
- Disease-free survival. Time to any event, irrespective of cause. All events are included, except loss to follow-up.
- Relapse-free survival. Time to any event, irrespective of cause, except for any second primary cancers. Recurrence of or death from the same cancer and all treatment-related deaths or deaths from other causes are events. Second primary same cancers and other primary cancers are ignored, and loss to follow-up is censored.
- Time to recurrence. Time to any event related to the same cancer. All same cancer recurrences and deaths from the same cancer are events. Second primary same cancers and other primary cancers are ignored. Deaths from other cancers, non–cancer-related deaths, treatment-related deaths, and loss to follow-up are censored observations.
- Time to treatment failure. Time to any event, except non–cancer-related death. All recurrences, treatment-related deaths, second same or other primary cancers, and deaths from other cancers are considered to be events. Loss to follow-up and non–cancer-related deaths are censored.
- Cancer-specific survival. Time to death caused by the same cancer, whether due to the original tumor or to a second primary same cancer. The only event is death from the same cancer, without taking into account whether the death is caused by the primary tumor or a second same cancer. Locoregional recurrence, distant metastases, second primary same cancers, and second other primary cancers are ignored. Deaths from other cancers, non–cancer-related deaths, treatment-related deaths, and loss to follow-up are censored.
- Overall survival. Time to death, irrespective of cause. There is no need to specify whether the death was due to cancer. Locoregional recurrence, distant metastases, second primary colorectal cancers, and second other primary cancers are ignored. Loss to follow-up is censored.
- Relapse-free survival. Time to any event, irrespective of cause, except for any second primary cancers. Recurrence of or death from the same cancer and all treatment-related deaths or deaths from other causes are events. Second primary same cancers and other primary cancers are ignored, and loss to follow-up is censored.
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After considering all six endpoints, the panel selected disease-free survival as defined in Table 2 as the most appropriate primary endpoint for future trials of adjuvant treatment for colon cancer or for any type of cancer. This endpoint was selected because it includes all clinically relevant events, has little opportunity for bias, is observed earlier than overall survival, and is likely to be statistically sensitive to real treatment benefits. Time to recurrence was identified as the most sensitive endpoint to evaluate the specific benefits of a new treatment because it excludes non–cancer-related death, and the panel recommended that this outcome should be evaluated as a secondary endpoint. The panel agreed that the starting point for each endpoint should be as unbiased as possible. Because the interval between the date of surgery and date of randomization may vary considerably and because most protocols require that patients have to start with adjuvant treatment within a specified short interval after the date of randomization, the panel considered the date of randomization to be the most appropriate starting point for each endpoint.
In conclusion, published studies on the adjuvant treatment of colon cancer showed marked heterogeneity in the definitions of endpoints other than overall survival, used different starting points for the calculation of interval to the event of interest, and/or did not provide any definition for these parameters. We propose standard definitions for the most frequently used endpoints based on the consensus of an expert panel. These definitions should contribute to a more uniform design of adjuvant studies in cancer, thereby allowing more consistent and better cross-study comparisons of results. We used colon cancer as a model because this cancer type is common and has been the focus of many recent trials of adjuvant therapies involving large numbers of patients. The differences we observed are likely to exist in adjuvant studies for other cancer types as well, however, and the outcome of this project may serve as a model for adjuvant treatment in other solid tumors.
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Funding |
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TopAbstractSystematic review of the...Consensus on endpoints and...FundingReferencesNotes |
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Supported by an unrestricted research grant from Pfizer. The funder had no role in either the design of the study, the analysis and interpretation of the data, the decision to publish, or the writing of the study.
Funding to pay the Open Access charges for this paper were provided by the Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
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NOTES |
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TopAbstractSystematic review of the...Consensus on endpoints and...FundingReferencesNotes |
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This paper resulted from a workshop that was held during the European Multidisciplinary Colorectal Cancer Congress in Berlin, February 2006.
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Manuscript received January 16, 2007; revised April 23, 2007; accepted May 22, 2007.
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J Natl Cancer Inst 2007 99: 981.
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