Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials

Daniel J. Sargent, Harry S. Wieand, Daniel G. Haller, Richard Gray, Jacqueline K. Benedetti, Marc Buyse, Roberto Labianca, Jean Francois Seitz, Christopher J. O'Callaghan, Guido Francini, Axel Grothey, Michael O'Connell, Paul J. Catalano, Charles Blanke, David Kerr, Erin Green, Norman Wolmark, Thierry Andre, Richard M. Goldberg, Aimery De Gramont

Research output: Contribution to journalArticle

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Abstract

Purpose: A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods: Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results: The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion: In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

Original languageEnglish (US)
Pages (from-to)8664-8670
Number of pages7
JournalJournal of Clinical Oncology
Volume23
Issue number34
DOIs
StatePublished - 2005
Externally publishedYes

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Colonic Neoplasms
Disease-Free Survival
Survival
Clinical Trials
Recurrence
Colon
Fluorouracil
Sample Size

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies : Individual patient data from 20,898 patients on 18 randomized trials. / Sargent, Daniel J.; Wieand, Harry S.; Haller, Daniel G.; Gray, Richard; Benedetti, Jacqueline K.; Buyse, Marc; Labianca, Roberto; Seitz, Jean Francois; O'Callaghan, Christopher J.; Francini, Guido; Grothey, Axel; O'Connell, Michael; Catalano, Paul J.; Blanke, Charles; Kerr, David; Green, Erin; Wolmark, Norman; Andre, Thierry; Goldberg, Richard M.; De Gramont, Aimery.

In: Journal of Clinical Oncology, Vol. 23, No. 34, 2005, p. 8664-8670.

Research output: Contribution to journalArticle

Sargent, DJ, Wieand, HS, Haller, DG, Gray, R, Benedetti, JK, Buyse, M, Labianca, R, Seitz, JF, O'Callaghan, CJ, Francini, G, Grothey, A, O'Connell, M, Catalano, PJ, Blanke, C, Kerr, D, Green, E, Wolmark, N, Andre, T, Goldberg, RM & De Gramont, A 2005, 'Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials', Journal of Clinical Oncology, vol. 23, no. 34, pp. 8664-8670. https://doi.org/10.1200/JCO.2005.01.6071
Sargent, Daniel J. ; Wieand, Harry S. ; Haller, Daniel G. ; Gray, Richard ; Benedetti, Jacqueline K. ; Buyse, Marc ; Labianca, Roberto ; Seitz, Jean Francois ; O'Callaghan, Christopher J. ; Francini, Guido ; Grothey, Axel ; O'Connell, Michael ; Catalano, Paul J. ; Blanke, Charles ; Kerr, David ; Green, Erin ; Wolmark, Norman ; Andre, Thierry ; Goldberg, Richard M. ; De Gramont, Aimery. / Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies : Individual patient data from 20,898 patients on 18 randomized trials. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 34. pp. 8664-8670.
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abstract = "Purpose: A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods: Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results: The recurrence rates for years 1 through 5 were 12{\%}, 14{\%}, 8{\%}, 5{\%}, and 3{\%}, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91{\%} of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92{\%}) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion: In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.",
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T1 - Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies

T2 - Individual patient data from 20,898 patients on 18 randomized trials

AU - Sargent, Daniel J.

AU - Wieand, Harry S.

AU - Haller, Daniel G.

AU - Gray, Richard

AU - Benedetti, Jacqueline K.

AU - Buyse, Marc

AU - Labianca, Roberto

AU - Seitz, Jean Francois

AU - O'Callaghan, Christopher J.

AU - Francini, Guido

AU - Grothey, Axel

AU - O'Connell, Michael

AU - Catalano, Paul J.

AU - Blanke, Charles

AU - Kerr, David

AU - Green, Erin

AU - Wolmark, Norman

AU - Andre, Thierry

AU - Goldberg, Richard M.

AU - De Gramont, Aimery

PY - 2005

Y1 - 2005

N2 - Purpose: A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods: Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results: The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion: In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

AB - Purpose: A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods: Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results: The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion: In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

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