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National Surgical Adjuvant
Breast and Bowel Project
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Oxaliplatin, Fluorouracil, and Leucovorinas Adjuvant Treatment for Colon Cancer
Thierry André, M.D., Corrado Boni, M.D., Lamia Mounedji-Boudiaf, M.D.,Matilde Navarro, M.D., Josep Tabernero, M.D., Tamas Hickish, M.D.,Clare Topham, M.D., Marta Zaninelli, M.D., Philip Clingan, M.D., John Bridgewater, M.D., Isabelle Tabah-Fisch, M.D.,and Aimery de Gramont, M.D., for the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatmentof Colon Cancer (MOSAIC) Investigators
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Mayo v. RPMIBolus v. Infusion of 5FUEfficacy of levamisoleHigh v. Low dose levamisole, LVDukes’ B v CAmerican v. European
Advocacy neglectConsensus statement abstinencePaucity of trials
1993-2003: A Decade of Decadence
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Two Steps Forward in the Treatment of
Colorectal Cancer
EDITORIALNew England Journal of Medicine
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Curative Options for Colorectal Cancer:
Folklore, fables, and mythes
Curative Options for Colorectal Cancer:
Folklore, fables, and mythes
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Variations on a theme of B (minor)
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On November 4, 2004, the FDA approved oxaliplatin in combination with infusional FULV for adjuvant stage III colon cancer.
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The Global test for interaction between treatment and tumor stage (II+III)
was not significant (p=0.71)
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INT 0035
’85-’87
Dukes B Dukes CControl Control
FU+LEV FU+LEV
LEV
n=318 n=929
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NSABP
Death Recurrence DFS event
Stage II
0.5 1 2.0 0.5 1 2.0 0.5 1 2.0
All patients
Stage III
Pooled analysis of NSABP C-01 through C-04
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INT 0035 Dukes BRFS
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9
159159
ContFuLev
%
P = 0.10
Yrs.
70
78
4532
31% reduction in recurrenceSource: Moertel CG et al. J Clin Oncol 1995;13(12):2936-43.
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COMBINED ANALYSIS 11.77-12.90
C-01
C-02
C-03
C-04
OP
OP
MOF
FU+LEV
MOF
PVI
FU+LV
FU+LV
Treatment 1 Treatment 2
N = 1924 N = 1896
Vs
Vs
Vs
Vs
0.05
0.02
<0.001
0.03
JCO 1999;17:1349
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PATIENT POPULATION
DUKES’ B 1567
DUKES’ C 2254
JCO 1999;17:1349
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American Society of Clinical OncologyRecommendations on Adjuvant Chemotherapy forStage II Colon Cancer
Al B. Benson III, Deborah Schrag, Mark R. Somerfield, Alfred M. Cohen, Alvaro T. Figueredo, Patrick J. Flynn, Monika K. Krzyzanowska, Jean Maroun, Pamela McAllister, Eric Van Cutsem, Melissa Brouwers, Manya Charette, and Daniel G. Haller
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'Uncertain indication'for chemotherapy
(3239 patients ’94 -’03 MTS 4.6 yrs)
Observation(n=1617)
FULV ± Lev(n=1622)
Randomize
Quick & Simple & Reliable
Richard G. Gray MS92% Dukes B
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Quasar Survival
n dths 5yS p Chemo 1622 281 80.3 0.02None 1617 328 77.4
Source: With permission. Gray RG et al. Presentation. ASCO 2004. Abstract 3501.
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Quasar Dukes B Survival
dths p Chemo 224 0.04None 262
Source: With permission. Gray RG et al. Presentation. ASCO 2004. Abstract 3501.
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Stage II: Putative Prognostic Discriminates
MSIAllelic instability (18q del)Venous invasionT differentiationNumber N examined (ignored or absent)High Risk Stage IIMayo algorithm
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Gene Identification: C-01/C-02
Univariate analysis
142 of 757 genes were associated with RFS (p<0.05)
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Gene Identification: C-01/C-02
Multivariate analysis Individual Genes# Pos NodesTumor GradeTumor Location
66 of the 142 genes retained independent significance (p<0.05)
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0102030405060708090
100
1% 3% 5% 10% 20% >20%
% risk reduction
Survey: N=150 pt with CRCC
um
% r
ec t
reat
men
t
Love N. Asco GI 2006
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Survey: N=150 pt with CRC
Love N. Asco GI 2006 # 373
FFox68%
Cape21%
FU10%
None 1%
Stage II
FFox87%
6%6%
None 1%
Stage III
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33
6772
94 92 96
0102030405060708090
100
10% 20% 30%
% risk reduction
Survey: N=100 Medical Oncologists%
lik
ely
to t
reat
Love N. Asco GI 2006
BreastCRC