The DOI matches its Crossref record; 33 of the 34 references it cites were found in a registry or an index.
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
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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“The validity of this approach, though not uncontroversial [13], is relatively well supported by data derived from a wide range of solid tumour settings including in colon [14], gastric [15], lung [16] and breast [17] cancers.”
Citations
Cites
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Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer
Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032691 · Cited by 10,968
Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer
André, T., Boni, C., Mounedji-Boudiaf, L., Navarro, M., Tabernero, J. M., Hickish, T., Topham, C., Zaninelli, M., Clingan, P. R., Bridgewater, J. A., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032709 · Cited by 3,694
A leisurely look at the bootstrap, the jackknife, and cross-validation
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Irinotecan plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer
Saltz, L. B., Cox, J. V., Blanke, C. D., Rosen, L. S., Fehrenbacher, L., Moore, M. J., Maroun, J. A., Ackland, S. P., Locker, P. K., Pirotta, N., et al. (2000) · New England Journal of Medicine · doi:10.1056/nejm200009283431302 · Cited by 3,004
Levamisole and Fluorouracil for Adjuvant Therapy of Resected Colon Carcinoma
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Items 701–713 of 713
Did ATOMIC really improve on the standard of care for mismatch repair-deficient colon cancer?
Fuentes, J. D. B., Karikios, D. J., & Gyawali, B. (2026) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-026-01154-x
“However, this relationship from the fluoropyrimi-dine era (reported in 2005) 4 was already less robust in the oxaliplatin era (reported in 2020) 5 ; therefore, whether this surrogacy holds in the modern era remains uncertain.”
Sekita, T., Akagi, T., Sadachi, R., Hasegawa, T., Shiroshita, H., Fukuda, H., Suto, T., Shiomi, A., Shiozawa, M., Tsukamoto, S., et al. (2026) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyag084
“The primar y endpoint is RFS, which has been validated as a surrogate for OS in adjuvant CRC trials by Sargent et al. [ 21].”
Kawabata, K., Matsuda, S., Tsushima, T., Ishiyama, K., Ishikawa, Y., Machida, R., Uozumi, T., Sasaki, K., Fukuda, H., Kato, K., et al. (2026) · European Journal of Surgical Oncology · doi:10.1016/j.ejso.2026.111962
Karimi, A., Ahmadinezhad, M., Hosseini, S. A., ahmadikia, S., Hajialigol, A., Mohammadzadeh, S., & Ahmadinejad, I. (2026) · Research Square · doi:10.21203/rs.3.rs-9960149/v1
Huang, S., Hsu, C.-W., Wu, C., & Chen, Y. S. (2026) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.70427
“…number of deaths in the landmark cohort was limited ( n = 19, with only 2 in the IV-Only group), insufficient for meaningful between-group comparison; additionally, the follow-up duration may be insufficient to capture long-term survival differences that emerge years after adjuvant therapy [28].”
Statistics of Randomized Clinical Trials
Nguyen, T., Liu, C., Ni, L., & Xie, R. (2026) · Springer eBooks · doi:10.1007/978-3-032-19175-5_11
Adjuvant Chemotherapy and Follow-Up
Leone, F. (2010) · Updates in surgery/Updates in surgery series · doi:10.1007/978-88-470-1809-9_10
Tang, S., Zang, H., Mao, L., Liu, X., & Li, X. (2026) · The Oncologist · doi:10.1093/oncolo/oyag342
“50 Melanoma analyses also show that patient-level association may exceed trial-level treatment–effect association and have not established a universal checkpoint-inhibitor RFS surrogate.”
Molecular residual disease: Charting a new path for treating resectable solid tumors
Kobayashi, S., Hashimoto, T., Bando, H., Nakamura, Y., Parikh, A., Tie, J., Shi, Q., Oki, E., & Yoshino, T. (2026) · Cancer Cell · doi:10.1016/j.ccell.2026.08.001
Çelebi, A., Meral, E., Akagündüz, F., Demirel, A., Tunç, M. A., Paçacı, B., Kocaaslan, E., Güren, A. K., Işık, S., Çoban, E., et al. (2026) · Medicina · doi:10.3390/medicina62101846
“The primary endpoint was recurrence-free survival (RFS), defined as the time from surgery to confirmed local or distant recurrence; patients dying without confirmed recurrence were censored at the date of death [17,18].”
Jo, M. H., Kang, K.-M., Choi, M. J., Shin, H.-R., Lee, T.-G., Ahn, H., Oh, H., Kim, D., & Kang, S. (2026) · Annals of Coloproctology · doi:10.3393/ac.2026.00325.0046
“Secondary outcomes included disease-free survival (DFS), defined as the time from surgery to the first documented recurrence (locoregional or systemic) or death from any cause, and overall survival (OS), defined as the time from surgery to death from any cause [15].”
Cancer du côlon : bilan et surveillance
Drouillard, A., & Lepage, C. (2014) · ONCOLOGIE · doi:10.1007/s10269-014-2471-2
“Elles sont d’autant plus précoces que le stade initial est avancé [10,34].”
BackgroundTherapeutic Counseling for the Medical Management of Renal Cell Carcinoma
Inman, B. A., & Leibovich, B. C. (2008) · Springer eBooks · doi:10.1007/978-1-84628-763-3_54
Metadata
- Authors
- Sargent, D. J., Wieand, H. S., Haller, D. G., Gray, R., Benedetti, J. K., Buyse, M., Labianca, R., Seitz, J. F., O'Callaghan, C. J., Francini, G., Grothey, A., O'Connell, M., Catalano, P. J., Blanke, C. D., Kerr, D., Green, E., Wolmark, N., Andre, T., Goldberg, R. M., & De Gramont, A.
- Affiliations
- University of Siena (IT)
- From the North Central Cancer Treatment Group, Mayo Clinic, Rochester, MN; National Surgical Adjuvant Breast and Bowel Project Statistical Center and Operations Office, Pittsburgh; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; QUASAR Collaborative Group, Birmingham and Oxford, United Kingdom; Southwest Oncology Group Statistical Center, Seattle, WA; International Drug Development Institute, Brussels, Belgium; Ospedali Riuniti, Bergamo; University of Siena, Siena, Italy; University...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2005-12-01
- Volume
- 23
- Issue
- 34
- Pages
- 8664-8670
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2172116130
- Cited by
- 713
- References
- 34
- Citations by year
- 2026: 19 · 2025: 14 · 2024: 19 · 2023: 20 · 2022: 34 · 2021: 32 · 2020: 27 · 2019: 20 · 2018: 24 · 2017: 30 · 2016: 26 · 2015: 40 · 2014: 36 · 2013: 40 · 2012: 44
- FWCI
- 48.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Document Server@UHasselt (UHasselt) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Funders
- National Cancer Institute ((CA-25224, U10CA025224)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- colon cancer, adjuvant chemotherapy, disease-free survival, overall survival, primary endpoint, surrogate endpoints, hazard ratio correlation, recurrence, individual patient data pooling
- MeSH terms
- Aged, Antineoplastic Combined Chemotherapy Protocols, Colonic Neoplasms, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Regression Analysis, Randomized Controlled Trials as Topic, Treatment Outcome, Chemotherapy, Adjuvant, Disease-Free Survival
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