Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803.
BACKGROUND
The ACCENT group previously established disease-free survival (DFS) with 2 or 3 years median follow-up to predict 5 year overall survival (5 year OS) in stage II and III colon cancer. ACCENT further proposed (1) a stronger association between DFS and OS in stage III than II, and (2) 6 or 7 years necessary to demonstrate DFS/OS surrogacy in recent trials. The relationship between end-points in trials with oral fluoropyrimidines, oxaliplatin and irinotecan is unknown.


METHODS
Associations between the treatment effect hazard ratios (HRs) on 2 and 3 years DFS, and 5 and 6 years OS were examined in 6 phase III trials not included in prior analyses from 1997 to 2002. Individual data for 12,676 patients were analysed; two trials each tested oxaliplatin, irinotecan and oral treatment versus 5-FU/LV.


RESULTS
Overall association between 2/3 year DFS and 5/6 year OS HRs was modest to poor (simple R² measures: 0.58-0.76, model-based R²: 0.17-0.49). In stage III patients, the association increased (model-based R² ≥ 0.79). Observed treatment effects on 2 year DFS accurately 5/6 year OS effects overall and in stage III patients.


CONCLUSIONS
In recent trials of cytotoxic chemotherapy, 2 or 3 years DFS HRs are highly predictive of 5 and 6 years OS HRs in stage III but not stage II patients. In all patients the DFS/OS association is stronger for 6 year OS, thus at least 6 year follow-up is recommended to assess OS benefit. These data support DFS as the primary end-point for stage III colon cancer trials testing cytotoxic agents.
NCCTG, Mayo Clinic, Rochester, MN, USA. sargent.daniel@mayo.edu
D
D
Sargent
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Q
Shi
G
G
Yothers
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E
Van Cutsem
J
J
Cassidy
L
L
Saltz
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N
Wolmark
B
B
Bot
A
A
Grothey
M
M
Buyse
A
A
de Gramont
D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017326:Clinical Trials, Phase III as Topic; D003110:Colonic Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D006801:Humans; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D016016:Proportional Hazards Models; D011743:Pyrimidines / Q000008:administration & dosage*; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome
D009944:Organoplatinum Compounds; D011743:Pyrimidines; D000077150:Oxaliplatin; D000077146:Irinotecan; D002166:Camptothecin
N Engl J Med. 2005 Jun 30;352(26):2696-704
15987918
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19451425
J Clin Oncol. 2008 May 10;26(14):2336-41
18467725
J Clin Oncol. 2007 Jun 1;25(16):2198-204
17470851
J Clin Oncol. 2009 Feb 20;27(6):872-7
19124803
N Engl J Med. 2004 Jun 3;350(23):2343-51
15175436
N Engl J Med. 1990 Feb 8;322(6):352-8
2300087
Stat Methods Med Res. 2008 Oct;17(5):529-35
18285442
J Clin Oncol. 2009 Jul 1;27(19):3109-16
19451431
J Clin Oncol. 2010 Jan 20;28(3):460-5
20008641
J Clin Oncol. 2006 May 1;24(13):2059-64
16648506
J Clin Oncol. 2007 Aug 10;25(23):3456-61
17687149
J Clin Oncol. 2005 Dec 1;23(34):8664-70
16260700
J Clin Oncol. 2009 Aug 1;27(22):3677-83
19470929
J Clin Oncol. 2007 Oct 10;25(29):4569-74
17876008