2

Key Points: What Works?

• Adjuvant therapy for colon cancer: the first step ! 5FU + Levamisole then Leucovorin

• Oral fluoropyrimidines, capecitabine and UFT are equivalent to 5-FU/LV

• Oxaliplatin plus fluoropyrimidines is better than fluoropyrimidines alone: the second step !

• Can elderly patients benefit from adjuvant therapy ?

3

The First Step (5FU)

Studies Treatment 3-year DFSMoertel 1 Observation 52%

IMPACT 2 Observation 44%

Moertel 1 5FU/Lev 64%

IMPACT 2 5FU/LV 62%

MOSAIC 3 LV5FU2 65%

X-Act 4 FUFOL 61%

XELOXA 5 FUFOL 66%

No treatment

FU + LV or Lev

1 Moertel CG, N Engl J Med 1990 2 IMPACT investigators, Lancet 19953 André T, J Clin Oncol 20094 Twelves C, N Engl J Med 2005 5 Haller D, J Clin Oncol 2011

1 Moertel CG, N Engl J Med 1990 2 IMPACT investigators, Lancet 19953 André T, J Clin Oncol 20094 Twelves C, N Engl J Med 2005 5 Haller D, J Clin Oncol 2011

DFS at 3 Years (Stage III)

5FU was discovered by C Heidelberger in 1957

4

DFS

1996: 5FU bolus + LV

Francini 1994IMPACT 1995 NCCTG 1997NCCTG-NCIC 1998INT 0089 1998NSABP C04 1999QUASAR 2000

Moertel

Adjuvant Therapy Stage III

6 months = 12 months

Leucovorin demonstrated synergy with 5FU in 1992 (D Machover)

1990: 5FU levamisole1990: 5FU levamisole

Machover D, J Natl Cancer Inst 1992Machover D, J Natl Cancer Inst 1992

Machover D, J Natl Cancer Inst 1992Machover D, J Natl Cancer Inst 1992

5

5FU Increases OS and Cure Patients:

Stage III CC

Sargent D, J Clin Oncol 2009

p<0.0001

Surgery alone8-year OS rate (95% CI): 42.7%(39.9% to 45.7%)

Surgery + FU-based chemotherapy8-year OS rate (95% CI): 53.0%(50.2% to 55.9%)

0 1 2 3 4 5 6 7 8

Follow-up time (years)

OS

est

imat

e1.0

0.8

0.6

0.4

0.2

0

10.3%

Evidence in 13,793 Patients with Stage III

6

5FU+lev

DFS

5FU bolus + LV

Adjuvant Therapy Stage III

LV5FU2/5FU protracted infusion

UK intergroup, Saini A et al. Br J Cancer 2003GERCOR 96-1, André T et al. J Clin Oncol, 2003PETTACC 2

Capecitabine

NSABPC06, Lambersky BC, J Clin Oncol 2006

UFT+LV

X-Act, Twelves C, N Engl J Med 2005

Better tolerance

7

Oral FluoroP in Adjuvant Setting

DFS

capecitabine 64.2%

FU-LV 60.6%

n DFS

UFT-LV 782 74.5%LV-LV 771 74.5%

100

80

60

40

20

00 1 2

Year

% D

FS

3

p=0.0528

100

80

60

40

20

00 1 2 3 4

Year

DFS

% O

S5 6

p = 0,88

DFS

HR = 0.87 (95% CI: 0.75–1.00)

Twelves,C et al. N. Engl. J. Med. 2005  Lembersky BC, J Clin Oncol 2006

X-ACT

(n=1987, only stage 3)

X-ACT

(n=1987, only stage 3)

End Point: DFS at 3 years

NSABP-C06 (n=1608, stage 2 & 3)

8

DFS at 3-years is the New Endpoint for Adjuvant Colon Cancer Studies:

• 3-year DFS excellent predictor of 5-year OS

• These data support use of 3-year DFS as primary endpoint in trials testing adjuvant therapy in colon cancer

• May 2004: ODAC recommends3-yr DFS as new regulatory endpoint for FULL approval in adjuvant colon cancerHR: 3-Year DFS vs 5-Year OS

Sargent D, J Clin Oncol.2005 

Data from Randomized Trials

9

The Second Step (2004): The Second Step (2004):

R

LV5FU2

FOLFOX4: LV5FU2 + oxaliplatin

N=2246

Stage 2 (40%) low-risk 15% high-risk (25%)

Stage 3 (60%) <4N (44.5%) ≥4N (15.1%)

MOSAIC: Study design

RFLOX : FUFOL Roswell Park and oxaliplatin

FUFOL Roswell Park

N=2407

Stage 2: 29%

Stage 3: 71% N1 (46% ) N2 (26%)

NSABP C07: Study design

1 André T, N Engl J Med 20042 Yothers G , J Clin Oncol 20113 Haller D, J Clin Oncol 2011

1 André T, N Engl J Med 20042 Yothers G , J Clin Oncol 20113 Haller D, J Clin Oncol 2011

Oxaliplatin + FluoroP (3 Studies)

R

FUFOL Mayo or Roswell Park

XELOX: capecitabine + o xaliplatin

N=1886

XELOXA N016968: Study design

Primary end-point for these 3 steudies: Disease-free Survival

Primary end-point for these 3 steudies: Disease-free Survival

10

DFS by Treatment Arm All Patients (ITT) Stage II and III

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 (months)

Probability

Hazard ratio: 0.77 [0.65 – 0.91] p =0.002

23% risk reduction in the FOLFOX4 arm

3-year DFS

André T, N Engl J Med 2004

5.3%

MOSAIC 2004

FOLFOX4 (n=1123)LV5FU2 (n=1123)

78.2%72.9%

11

DFS at 3 Years (ITT) Stage III Patients

FOLFOX4 – 672 Stage IIILV5FU2 – 675 Stage III

HR [95% CI]:0.76 [0.62 – 0.92] Stage III

1.0

0.9

0.8

0.7

0.6

0.5

0.3

0.4

0.2

0.1

Months

DF

S r

ate

0 666 12 18 24 30 36 42 48 54 60

MOSAIC 2004MOSAIC 2004

DFS Survival rate at 3 years

72.2% for FOLFOX4

65.3% for LV5FU2

DFS Survival rate at 3 years

72.2% for FOLFOX4

65.3% for LV5FU2

André T, N Engl J Med 2004André T, N Engl J Med 2004

6.9%

12

Overall Survival: Stage II and Stage III

Data cut-off: January 2007

Overall survival (months)

Pro

bab

ilit

y

André T, J Clin Oncol 2009

MOSAIC 2004

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

HR [95% CI]

Stage II 1.00 [0.70–1.41]

Stage III 0.80 [0.65–0.97]

p=0.996

p=0.029

Stade II

Stade III 0.1%

4.2%

13

Fluoropyrimidines ± Oxaliplatin Stage III

HR for DFS

P value DFS Delta (%)

HR for OS P value OS Delta (%)

MOSAIC (1)

0.78CI, 0.65-0.93

At 5 year

0.005 7.5%58.9% vs 66.4%

At 5 year

0.80CI, 0.65-0.97

At 6 year

0.023 4.2%68.7% vs 72.9%

At 6 year

NSABP C-07(2)

0.78CI, 0.68-0.90

At 5 year

0.0007 6.6 %

57.8% vs 64.4%At 5 year

0.85CI, 0.72-1.00

At 5 year

0.052 2.7%73.8% vs 76.5%

At 5 year

XELOXA(3)

0.80CI, 0.69-0.93

At 3 year

0.0045 4.4%66.5% vs 70.9%

At 3 year

0.87CI, 0.72-1.05

At 5 year

0.1486 3.4%ND

(57 months FU)

1 André T, J Clin Oncol. 20092 Yothers G, J Clin Oncol 20113 Haller D, J Clin Oncol 2011

1 André T, J Clin Oncol. 20092 Yothers G, J Clin Oncol 20113 Haller D, J Clin Oncol 2011

Evidence Based Medicine

14

Years

No benefit of chemotherapy

Cured bychemotherapyFluoroP + oxali

Already cured by surgery

Adjuvant Therapy for Colon Cancer Stage III

0

20

40

60

80

100

0 1 2 3 4 5

expo

sed to

toxicity

Surgery alone

Surgery plus Chemotherapy

20%

%

Dis

ease

Fre

e S

urv

ival

60%

20%

20%

20%

Moertel CG, N Engl J Med 1990 IMPACT investigators, Lancet 1995André T, J Clin Oncol. 2009Yothers G, J Clin Oncol 2011Haller D, J Clin Oncol 2011

Moertel CG, N Engl J Med 1990 IMPACT investigators, Lancet 1995André T, J Clin Oncol. 2009Yothers G, J Clin Oncol 2011Haller D, J Clin Oncol 2011

15

Grade 3/4 FOLFOX41

N=1123

FLOX2

N=1247

XELOX3

N=944

mFOLFOX64

N=1321

Neutropenia 40% NR 9% 33%

Febrile neutrop. <2% >2% <1% <2%

Platelets 2% NR 5% 3%

Diarrhea 11% 38% 19% 10%

Nausea 5% 16% 5% NR

HFS 2% NR 5% NR

Neuropathy 12% 8% 11% 14%

60 day Mortality 3 (0.3%) 15 (1.2%) 9 (1.0%) 12 (0.96%)

Within 6 months

Oxaliplatin/FluoroP Trials - Safety

Median oxaliplatin 810 mg/m2 (9.5 cycles) in the MOSAIC trial and 667 mg/m2 (7.8 cycles) in NSABP C-07 1 André T, J Clin Oncol. 2009; 2 Yothers G, J Clin Oncol 2011,

3 Haller D, J Clin Oncol 2011; 4 Allegra CJ, J Clin Oncol 2011

Median oxaliplatin 810 mg/m2 (9.5 cycles) in the MOSAIC trial and 667 mg/m2 (7.8 cycles) in NSABP C-07 1 André T, J Clin Oncol. 2009; 2 Yothers G, J Clin Oncol 2011,

3 Haller D, J Clin Oncol 2011; 4 Allegra CJ, J Clin Oncol 2011

16

Could mFOLFOX6 Regimen Replace FOLFOX4?

Cycles every 14 daysDose mg/m2 - LV m2 (l-LV 1/2 dose)

H0 H2 H24 H48

Oxali 85

FOLFOX4 5-FU 600 LV 400LV 400 5-FU 600LV 400LV 400

5FUb 4005FUb 400 5FUb 4005FUb 400

LV 400 5-FU 2400

Oxali 85

mFOLFOX6

5FUb 400

MOSAIC FOLFOX4: DFS at 3 years for stage 3: 72.2 %MOSAIC FOLFOX4: DFS at 3 years for stage 3: 72.2 %

NSABP C08 mFOLFOX6: DFS at 3 years for stage 3: 75.5 %NSABP C08 mFOLFOX6: DFS at 3 years for stage 3: 75.5 %

André T, N Engl J Med 2004Allegra CJ, J Clin Oncol 2011

André T, N Engl J Med 2004Allegra CJ, J Clin Oncol 2011

17

Can Elderly Patients Benefit From Adjuvant Therapy?

Can Elderly Patients Benefit From Adjuvant Therapy?

18

Can Elderly Patients Benefit from Adjuvant Therapy?: Yes for FluoroP!

Adjuvant setting (meta-analysis; N=3351 (15% ≥ 70 yrs)

DFS

OS

< 70 yrs > 70 yrs

Sargent D, NEJM 2001Sargent D, NEJM 2001

• 7 trials of 5-FU +

levamisole/leucovorin vs

surgery

• No significant interaction

observed between age and

efficacy of treatment

19

Toxicity in Elderly with Adjuvant CT (≥ 70 Years)

• If Fluoropyrimidines alone, except for leucopenia, the incidence of toxic effects of chemotherapy is not higher in elderly patients

• For capecitabine, be careful in elderly patients (need good renal function and good follow-up)

• FOLFOX was well tolerated in elderly patients with only a significant increase in Grade 3-4 hematologic toxicity: neutropenia [43% vs 49%; p=0.04] and thrombocytopenia [2% vs 5%; p=0.04]

Sargent D, NEJM 2001Goldberg R, J Clin Oncol 2006Sargent D, NEJM 2001Goldberg R, J Clin Oncol 2006

20

N>70 %DFS HR

And CIRFS HR OS HR reference

C-07 388 16.9 1.17

0.94 -1.46

- 1.32

1.03-1.70

Kuebler JP, J Clin Oncol 2007

MOSAIC 315 14.0 0.93

0.64-1.35

0.72

0.47–1.11

1.10

0.73-1.65

In press

Tournigand C, J Clin Oncol 2012

ACCENT

C-07 and MOSAIC

703 15.0 1.04

0.80-1.35

0.92

0.69 - 1.23

1.18

0.90 – 1.57

Mc Cleary NJ, ASCO 2009,

abstr 4010

XELOXA

NO16968

409 21.7 0.87

0.63-1.18

- 0.94

0.66-1.34

Haller D, ASCO GI 2010, abst 284

Treatment test interaction with age for DFS is not significant in C07 (p<0.05) and in MOSAIC (p=0.418) but is significant in the ACCENT meta-analysis of the 2 studies (p=0.016) suggesting that the effect of oxaliplatin in patients younger than 70 is different from the effect in patients aged 70 or older

Can Elderly Patients Benefit from Adj Therapy with Oxaliplatin?: No, but… !Can Elderly Patients Benefit from Adj Therapy with Oxaliplatin?: No, but… !

..

21

Adjuvant CT for Stage III in Elderly Patients (> 70 years)

• 6 months of FU and Leucovorin (Simplified LV5FU2 or capecitabine) are the standard of care

• no statistically significant benefit (OS and DFS) for adding oxaliplatin to FU and Leucovorin

• The patient population for whom adding oxaliplatin to FluoroP is justified needs to be identified in the elderly

22

Neuroprotection

• To prevent grade III sensory neuropathy: discontinuing oxaliplatin in case of grade 2 or 3

• Level of evidence (evidence-based medicine) regarding the utility of Ca/Mg infusion for preventing oxaliplatin-induced neuropathy is low and needs additional data1-2

• In case of acute sensory neuropathy, venlafaxine? Further prospective studies are needed3.

• Reduction in duration of chemotherapy is a way to reduce neurosensory neuropathy (IDEA: International Duration Evaluation of Adjuvant Chemotherapy) 1 Gamelin E, Clin Cancer Reseach 2004

2 Grothey A, J Clin Oncol 20113 Durand JP, Ann Oncol 2011

1 Gamelin E, Clin Cancer Reseach 20042 Grothey A, J Clin Oncol 20113 Durand JP, Ann Oncol 2011

23

Conclusion: Adjuvant Treatment for Stage III Colon Cancer in 2012:

Standard patients (< 70 years old)• 12 cycles of FOLFOX41 or mFOLFOX62 with oxaliplatin discontinuation

in case of neuropathy grade 2 – 3 (continuing with sLV5FU2)• or 8 cycles of XELOX2 (oxaliplatin 130 mg/m2 day 1 and capecitabine

bid 1000 mg/m² x 2; day 1-14/21)

Standard elderly (≥ 70 years old)• 5FU/LV (12 cycles of LV5FU2 simplified) • or 8 cycles of capecitabine alone (capecitabine 1000 to 1250 mg/m² x

2 for 14 days)1 André T, N Engl J Med 2004

2 Allegra CA, J Clin Oncol 20103 Haller D, J Clin Oncol 2011

4 Twelves, C et al. N. Engl. J. 2005 

What is the Standard?

24

Thank you for your attention