Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: Simulations based on the 20,800 patient ACCENT data set

Aimery De Gramont, Joleen Hubbard, Qian Shi, Michael J. O'Connell, Marc Buyse, Jacqueline Benedetti, Brian Bot, Chris O'Callaghan, Greg Yothers, Richard M. Goldberg, Charles Blanke, Al Benson, Qiqi Deng, Steven R. Alberts, Thierry Andre, Norman Wolmark, Axel Grothey, Daniel Sargent

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Purpose: We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association. Methods: The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed. Results: Seven thousand four hundred two patients (35%) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R 2 = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R2 = 0.67 for both 2- and 3-year DFS) and 7-year OS (R2 = 0.70 for both 2- and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings. Conclusion: Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials.

Original languageEnglish (US)
Pages (from-to)460-465
Number of pages6
JournalJournal of Clinical Oncology
Volume28
Issue number3
DOIs
StatePublished - Jan 20 2010
Externally publishedYes

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Colonic Neoplasms
Disease-Free Survival
Recurrence
Survival
Therapeutics
Datasets
Clinical Trials
Fluorouracil

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer : Simulations based on the 20,800 patient ACCENT data set. / De Gramont, Aimery; Hubbard, Joleen; Shi, Qian; O'Connell, Michael J.; Buyse, Marc; Benedetti, Jacqueline; Bot, Brian; O'Callaghan, Chris; Yothers, Greg; Goldberg, Richard M.; Blanke, Charles; Benson, Al; Deng, Qiqi; Alberts, Steven R.; Andre, Thierry; Wolmark, Norman; Grothey, Axel; Sargent, Daniel.

In: Journal of Clinical Oncology, Vol. 28, No. 3, 20.01.2010, p. 460-465.

Research output: Contribution to journalArticle

De Gramont, A, Hubbard, J, Shi, Q, O'Connell, MJ, Buyse, M, Benedetti, J, Bot, B, O'Callaghan, C, Yothers, G, Goldberg, RM, Blanke, C, Benson, A, Deng, Q, Alberts, SR, Andre, T, Wolmark, N, Grothey, A & Sargent, D 2010, 'Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: Simulations based on the 20,800 patient ACCENT data set', Journal of Clinical Oncology, vol. 28, no. 3, pp. 460-465. https://doi.org/10.1200/JCO.2009.23.1407
De Gramont, Aimery ; Hubbard, Joleen ; Shi, Qian ; O'Connell, Michael J. ; Buyse, Marc ; Benedetti, Jacqueline ; Bot, Brian ; O'Callaghan, Chris ; Yothers, Greg ; Goldberg, Richard M. ; Blanke, Charles ; Benson, Al ; Deng, Qiqi ; Alberts, Steven R. ; Andre, Thierry ; Wolmark, Norman ; Grothey, Axel ; Sargent, Daniel. / Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer : Simulations based on the 20,800 patient ACCENT data set. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 3. pp. 460-465.
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abstract = "Purpose: We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association. Methods: The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed. Results: Seven thousand four hundred two patients (35{\%}) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R 2 = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R2 = 0.67 for both 2- and 3-year DFS) and 7-year OS (R2 = 0.70 for both 2- and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings. Conclusion: Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials.",
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T1 - Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer

T2 - Simulations based on the 20,800 patient ACCENT data set

AU - De Gramont, Aimery

AU - Hubbard, Joleen

AU - Shi, Qian

AU - O'Connell, Michael J.

AU - Buyse, Marc

AU - Benedetti, Jacqueline

AU - Bot, Brian

AU - O'Callaghan, Chris

AU - Yothers, Greg

AU - Goldberg, Richard M.

AU - Blanke, Charles

AU - Benson, Al

AU - Deng, Qiqi

AU - Alberts, Steven R.

AU - Andre, Thierry

AU - Wolmark, Norman

AU - Grothey, Axel

AU - Sargent, Daniel

PY - 2010/1/20

Y1 - 2010/1/20

N2 - Purpose: We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association. Methods: The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed. Results: Seven thousand four hundred two patients (35%) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R 2 = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R2 = 0.67 for both 2- and 3-year DFS) and 7-year OS (R2 = 0.70 for both 2- and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings. Conclusion: Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials.

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