National Surgical Adjuvant

Breast and Bowel Project

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

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

Two Steps Forward in the Treatment of

Colorectal Cancer

EDITORIALNew England Journal of Medicine

Curative Options for Colorectal Cancer:

Folklore, fables, and mythes

Curative Options for Colorectal Cancer:

Folklore, fables, and mythes

Variations on a theme of B (minor)

On November 4, 2004, the FDA approved oxaliplatin in combination with infusional FULV for adjuvant stage III colon cancer.

The Global test for interaction between treatment and tumor stage (II+III)

was not significant (p=0.71)

INT 0035

’85-’87

Dukes B Dukes CControl Control

FU+LEV FU+LEV

LEV

n=318 n=929

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

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.

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

PATIENT POPULATION

DUKES’ B 1567

DUKES’ C 2254

JCO 1999;17:1349

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

'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

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.

Quasar Dukes B Survival

dths p Chemo 224 0.04None 262

Source: With permission. Gray RG et al. Presentation. ASCO 2004. Abstract 3501.

Stage II: Putative Prognostic Discriminates

MSIAllelic instability (18q del)Venous invasionT differentiationNumber N examined (ignored or absent)High Risk Stage IIMayo algorithm

Gene Identification: C-01/C-02

Univariate analysis

142 of 757 genes were associated with RFS (p<0.05)

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)

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

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

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