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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