The evolving landscape of adjuvant treatment of colon cancer

Colon cancer survival rate

Stage (AJCC 6th Edition) 5-year survival (%)

I = T1 or T2, N0 93*No adjuvant treatment?

IIa = T3, N0 85* Eligible foradjuvant treatment

IIb = T4, N0 72*

IIIa = T1 or T2, N1 60†–83*Eligible for

adjuvant treatmentIIIb = T3 or T4, N1 42†–64*

IIIc = Tx, N2 27†–44*

*SEER database – O’Connell et al. J Natl Cancer Inst 2004 †US National Cancer Database – Greene et al. Ann Surg 2002

Nederlandse Richtlijn

• Bij patiënten met een hoog risico stadium II coloncarcinoom dient adjuvante chemotherapie te worden overwogen. Voor de chemotherapie keuze gelden dezelfde overwegingen als voor het stadium III.

Landelijke werkgroep Gastro Intestinale Tumoren, Versie: 2.0, Type: Landelijke richtlijn; 2009

Establishing effective adjuvant therapy

X-ACT

MOSAIC

XELOXA

Addition of oxaliplatinprolongs survival in stage III

Xeloda as the idealfluoropyrimidine backbone

XELOX is a new option for stage III

Establishing effective adjuvant therapy

X-ACT

MOSAIC

XELOXA

Addition of oxaliplatinprolongs survival in stage III

Xeloda as the idealfluoropyrimidine backbone

XELOX is a new option for stage III

X-ACT: Xeloda Adjuvant Chemotherapy Trial of stage III colon cancer

• Primary endpoint: non-inferiority in DFS

Bolus 5-FU/LV5-FU 425mg/m2 + LV 20mg/m2 d1–5

q4w

Xeloda1 250mg/m2 bid d1–14

q3w Chemotherapy-naive

stage IIIResection ≤8 weeks

n=1 987

RANDO MISATION

Twelves et al. ASCO GI 2008

0.4

X-ACT: trend to superior DFS with Xeloda

Xeloda (n=1 004)

5-FU/LV (n=983)

Years

5-year DFS (%)

60.8

56.7

0.6

0.8

1.0

1 2 3 4 5 6 7 8

Absolute differenceat 5 years: 4.1%

0

Estimated probability

ITT population

HR=0.88 (95% CI: 0.77–1.01)p=0.0682

Twelves et al. ASCO GI 2008

X-ACT: trend to superior OS with Xeloda

Years1 2 3 4 5 6 7 80

0.4

0.6

0.8

1.0Estimated probability

Absolute differenceat 5 years: 3.1%

HR=0.86 (95% CI: 0.74–1.01)p=0.0600

Xeloda (n=1 004)

5-FU/LV (n=983)

5-year OS (%)

71.4

68.4

ITT population Twelves et al. ASCO GI 2008

0

10

20

30

40

50

Neutropenia

Nausea/

vomiti

ng

Stom

atitis

Diarrhoea

Febrile

neutropenia HFS

Patients (%)

Scheithauer et al. Ann Oncol 2003

* * * *

*p<0.001

Xeloda (n=993)

5-FU/LV (n=974)

Grade 3 / 4 AEs

X-ACT:improved safety with Xeloda

X-ACT: Xeloda as the idealfluoropyrimidine backbone

• Effective – superior DFS and OS vs bolus 5-FU– equivalent to ci 5-FU in cross-trial comparison

• Superior safety vs bolus 5-FU

Establishing effective adjuvant therapy

X-ACT

MOSAIC

XELOXA

Addition of oxaliplatinprolongs survival in stage III

Xeloda as the idealfluoropyrimidine backbone

XELOX is a new option for stage III

MOSAIC – superior OS with adjuvant oxaliplatin in stage III patients

4 62 800.0

0.2

0.4

0.6

0.8

1.0

Estimated probability

FOLFOX4 (n=672)

LV5FU2 (n=675)

6-year OS (%)

73.0

68.6

HR=0.80 (95% CI: 0.66–0.98)p=0.029Absolute difference

at 6 years: 4.4%

André et al. J Clin Oncol 2009Years

Nederlandse Richtlijn

• FOLFOX is de standaard adjuvante chemotherapie bij het stadium III coloncarcinoom. Omdat het orale 5-FU analoge capecitabine minstens gelijkwaardig is in gemetastaseerde setting en het toxiciteitsprofiel, als monotherapie en in combinatieschema's, gunstiger is vergeleken met 5-FU, kan ook in adjuvante schema's 5-FU vervangen worden door capecitabine.

Landelijke werkgroep Gastro Intestinale Tumoren, Versie: 2.0, Type: Landelijke richtlijn; 2009

Establishing effective adjuvant therapy

X-ACT

MOSAIC

XELOXA

Addition of oxaliplatinprolongs survival in stage III

Xeloda as the idealfluoropyrimidine backbone

XELOX is a new option for stage III

Chemo/radiotherapy-naive

stage III colon cancer

n=1 886 Bolus 5-FU/LVMayo Clinic or Roswell Park

XELOXXeloda 1 000mg/m2 bid d1–15

oxaliplatin 130mg/m2 d1q3w

• Primary endpoint: superiority in DFS

n=944

n=942

Schmoll et al. J Clin Oncol 2007

RANDO MISATION

XELOXA (NO16968): XELOX –a new option in the adjuvant setting

Safety

Grade 3/4 AEs (%)XELOXn=938

5-FU/LVn=926

Febrile neutropenia 0.4 4.2

Neutropenia 8.8 15.9

Diarrhoea 19.4 20.2

Stomatitis 0.6 8.9

Nausea 5.2 4.5

Vomiting 6.2 3.3

HFS 5.4 0.6

Neurosensory 11.4 0.1

Schmoll et al. JCO 2007

Cross-trial comparison with MOSAIC

Schmoll et al. JCO 2007*MOSAIC trial: André et al. NEJM 2004

Grade 3/4 AEs (%)XELOXn=938

FOLFOX4(MOSAIC)*

n=1108

Febrile neutropenia 0.4 1.8

Neutropenia 8.8 41.1

Diarrhoea 19.4 10.8

Stomatitis 0.6 2.7

Nausea 5.2 5.1

Vomiting 6.2 5.8

HFS 5.4 2.0

Neurosensory 11.4 12.4

Superior RFS with XELOX(excludes all non-cancer-related mortality)

ITT population

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

XELOX 5-FU/LV

72.1% 69.7%

3-yearRFS

67.5% 63.3%

4-yearRFS

5-yearRFS

60.9%67.8%

HR=0.78 (95% CI: 0.67–0.92)p=0.0024

Δ at 4 years: 6.4% Δ at 5 years: 6.9%

Δ at 3 years: 4.6%

Years

Immature Data:Trend to improved OS with XELOX

ITT population

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

XELOX 5-FU/LV

Δ at 5 years: 3.4%

HR=0.87 (95% CI: 0.72–1.05)p=0.1486

Years

77.6%

5-yearOS

74.2%

Years

2 4 6

0.4

0.6

0.8

1.0

0

0.4

0.6

0.8

1.0

Years

1. André et al. JCO 2009

8 2 4 60 8

Cross-trial comparison of MOSAICand XELOXA: OS in stage III disease

XELOX

5-FU/LV

FOLFOX4

LV5FU2

XELOXA(57 mo) MOSAIC1

(81.9 mo)

ITT population

1.0

0.6

0.8

1. André et al. JCO 2009

1 2 3 4 5 6 7 8

Cross-trial comparison of MOSAICand XELOXA: OS in stage III disease

Years

XELOX (n=944)

FOLFOX4 (n=672) –

5-yr OS 6-yr OS

72.9%

77.6%

NO16968 (XELOXA)*

MOSAIC1**

–

*Median observation time: 57.0 months**Median follow-up: 81.9 monthsITT population

0.4

0

Grade 3 / 4 AEsPatients (%)

XELOX1 (n=938)

FOLFOX42 (n=1 108)

FLOX3 (n=1 200)

Cross-trial comparison†Not reported

Neutropenia

Nausea

Stom

atitis

Diarrhoea

Febrile

neutropenia HFS

Vomiti

ng

Neurosensory

Adjuvant XELOX: favourable toxicity compared with FOLFOX4 and FLOX

† †

1. Schmoll et al. J Clin Oncol 20072. André et al. N Engl J Med 2004; 3. Kuebler et al. J Clin Oncol 2007

0

10

20

30

40

50

• Efficacy– XELOX significantly improves DFS and RFS compared

with bolus 5-FU/LV– trend to improved OS with XELOX; follow-up ongoing

• Favourable safety profile

• Ease of administration– fewer study visits, no pumps or catheters

• XELOX is a new option for patients with stage III colon cancer

XELOXA (NO16968): conclusions