Adjuvante therapie van het coloncarcinoom anno 2004-2005: is 5FU/LV nog steeds de standaard? Prof.dr. C.J.A. Punt afd. Medische Oncologie UMC St. Radboud.
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Adjuvante therapie van het coloncarcinoom anno 2004-2005:
is 5FU/LV nog steeds de standaard?
Prof.dr. C.J.A. Puntafd. Medische Oncologie
UMC St. RadboudNijmegen
Adjuvant therapy for colon cancerhot topics 2004
•FOLFOX
•Capecitabine
•Stage II
•Primary endpoint in randomised studies
Adjuvant therapy for stage III colon cancer - history
• 1990: 12 months 5FU/levamisole (absolute reduction of mortality = 13%)
• 1990: NIH consensus
• 1996: 6 months 5FU/LV is equivalent
• 2001: comparable benefit in elderly patients (>70 yrs)
•No preference for 5FU/LV schedule
Adjuvant therapy for colon cancer - new developments in 1990s
• Locoregional chemotherapy: no benefit
•Different schedules of 5FU/LV: no benefit
(3 months infusional 5FU 6 months 5FU/LV Mayo Clinic, Ann Oncol, in press)
•New modulators of 5FU (IFN!): no benefit
New drugs for adjuvant therapy in colon cancer since 1998
• Irinotecan
•Oxaliplatin
•Edrecolomab
• IFN
•Raltitrexed
•Capecitabine
•UFT/LV
•COX-2 inhibitors
•Signal transduction inhibitors (EGF-R,VEGF)
Irinotecan as adjuvant therapy in stage III colon cancer
•Bolus 5FU regimen with irinotecan (IFL) versus weekly 5FU/LV, n = 1254
•No benefit in DFS or OS
Data are accumulating that irinotecan should be combined with infusional and not bolus 5FU
Saltz et al. ASCO 2004
Overall survival as primary endpoint in adjuvant studies
• considered as gold standard until 2004
Disadvantages:
• long duration of studies
• poor compliance of investigators
• slow implementation of promising new therapies
•with inconsistent use of more effective drugs after recurrence, effect of adjuvant Rx difficult to assess
Disease-free survival as endpoint of adjuvant studies in colon cancer
•Pooled analysis of > 17.000 patients enrolled in 17 phase III adjuvant 5FU studies 1978 – 1996
• 34% stage II, 65% stage III
• 74% of recurrences < 3 years
•Excellent correlation between 3-yr DFS and 5-yr OS
Sargent et al. ASCO 2004
3-yrs disease-free survival as endpoint of adjuvant studies in colon cancer
Cautions:
•Proportion of stage II patients is increasing: overall prognosis will be better
•Meta-analysis restricted to 5FU. With new effective drugs available, median survival after recurrence will be longer, DFS in adjuvant setting may be prolonged
•DFS at 3 years may not remain the gold standard !!
Problems in studies with adjuvant therapy in stage II colon cancer
Large studies needed:
• at this stage relatively few events
• elderly population with relatively high incidence of non-cancer related deaths
• accrual in 90’s compromised by relatively low incidence of stage II disease
5FU/LV as adjuvant therapy for stage II colon cancer - history
result on survival
• IMPACT 6 studies n = 1100 negative
•NSABP 4 studies1 n = >2000 positive
•Mayo ’95 n = 318 negative
•CKVO ’012 n = 1029 positive
•QUASAR ’04 n = 3239 positive
1 2 studies without observation arm2 stage II and stage III colon+rectal
Adjuvant treatment in stage II colorectal cancer – QUASAR study
Gray et al. ASCO 2004
observation 5FU schedule
n 1617 1622
5-yr OS 77.4% 80.3% (p.02)
• Adjuvant treatment results in absolute 3% overall survival benefit in stage II colorectal cancer• No significant benefit in pts > 70 yrs
Adjuvant treatment in stage II colon cancer
•Data are accumulating that adjuvant treatment may be effective
•Absolute survival benefit for fluoropyrimidine treatment is approx. 3 – 4%
UFT/LV versus 5FU/LV (Roswell Park schedule) in stage II + III colon cancer
Wolmark et al. ASCO 2004
5FU/LV UFT/LV
n 777 784
5-yr DFS 68.3% 66.9%
5-yr OS 78.7% 78.7%
UFT/LV has equivalent efficacy and toxicity to 5FU/LV
X-ACT trial in adjuvant treatment of stage III colon cancer
• 1° endpoint: DFS
• 2° endpoints
• OS
• tolerability
• pharmacoeconomics
• QoL
Stage IIIresection <8 weeks
Capecitabine1 250 mg/m2 twice daily,
d1–14, q21d n=1 004
Bolus 5-FU/LV5-FU 425 mg/m2 plus
LV 20 mg/m2, d1–5, q28dn=983
24 weeks
X-ACT powered to establish at least equivalence of capecitabine to 5-FU/LV
• Primary endpoint DFS80% power for at least equivalence primary endpoint met if upper limit 95% CI HR <1.25
• Secondary analysestests for superiorityRFS, OSmultivariate and subgroup analyses
• All analyses shown were prospectively planned
X-ACT treatment arms were well balanced
Capecitabine (n=1 004) (%)
Bolus 5-FU/LV (n=983) (%)
Age, median (range) 62 (25–80) 63 (22–82)
ECOG 0/1 85 / 15 85 / 15
Male/female 54 / 46 54 / 46
CEA: normal / >ULN 83 / 9 84 / 7
T1–2 T3/T4
10 76 / 14
10 76 / 14
Nodal status: N1/2 70 / 30 71 / 29
Tumour differentiation Well/moderate Poor/anaplastic
9 / 65 16 / 1
10 / 63 19 / 1
Cassidy et al. ASCO 2004
DFS: primary endpoint achieved (ITT)
HR = 0.87 (95% CI: 0.75–1.00)
Capecitabine (n=1 004)
5-FU/LV (n=983)
Estimated probability
0 1 2 3 4 5 6
1.0
0.8
0.6
0.4
Years
Capecitabine showed trend to superior DFS (ITT)
Estimated probability
0 1 2 3 4 5 6
1.0
0.8
0.6
0.4
Absolute differenceat 3 years: 3.6%
p=0.0528
3-year DFS
Capecitabine (n=1 004) 64.2%
5-FU/LV (n=983) 60.6%
Years
Capecitabine showed trend to improved OS (ITT)
Estimated probability
0 1 2 3 4 5 6
Years
Absolute difference at 3 years: 3.7%
1.0
0.8
0.6
0.4
3-year OS
Capecitabine (n=1 004) 81.3%
5-FU/LV (n=983) 77.6%
HR = 0.84 (95% CI: 0.69–1.01)p=0.0706
Capecitabine consistent benefit in subgroup analysis for DFS
Hazard ratio and 95% CI
capecitabine better Bolus 5-FU/LV better
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
ITT population
MaleFemale
<40 40–69 years old≥70
N1 (1–3 nodes)N2 (4 nodes)
Baseline CEA <ULNBaseline CEA >ULN
1 987
1 074 912
76 1 543 396
1 389 593
1 672 155
n
1.0
0.8
0.6
0.4
0.2
0
Estimated probability of grade 3/4 adverse event
0 1 2 3 4 5 6 7 8Months
5-FU/LVcapecitabine
Grade 3/4 diarrhoea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia
p<0.001
Fewer key grade 3/4 toxicities and later onset with capecitabine
Adjuvant chemotherapy needs active management
Patients (%)
Capecitabine (n=995)
Bolus 5-FU/LV(n=974)
Completed full course of treatment
84 88
Needed dose reduction 42 44
Needed interruption 15 5
Needed delay 46 29
Needed dose reduction, interruption or delay
57 52
Cassidy et al. ASCO 2004
Capecitabine as adjuvant treatment in stage III colon cancer
Compared to 5FU/LV, capecitabine has:
• trend towards better DFS
• trend towards better OS
• improved safety (but is still cytotoxic treatment!)
Capecitabine should replace 5FU/LV as adjuvant treatment in stage III colon cancer
MOSAIC: Study Designstage II + III colon cancer
R
LV5FU2
FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²
Primary: – Disease-Free Survival (DFS)
Secondary:– Safety (including long-term)– Overall Survival (OS)
Endpoints
MOSAIC Rationale 1:MOSAIC Rationale 1:LV5FU2 in LV5FU2 in metastaticmetastatic colon cancer colon cancer
de Gramont et al. J Clin Oncol, 1997
5-FU infusion5-FU infusion 5-FU infusion5-FU infusion
D1D1 5-FU bolus5-FU bolus D2D2
LV LV
5-FU bolus5-FU bolus
Compared to monthly bolus 5-FU/LV: improved progression-free survival decreased toxicity
MOSAIC Rationale 2:MOSAIC Rationale 2:LV5FU2 in LV5FU2 in adjuvantadjuvant colon cancer colon cancer
André et al. J Clin Oncol, 2003
5-FU infusion5-FU infusion 5-FU infusion5-FU infusion
D1D1 5-FU bolus5-FU bolus D2D2
LV LV
5-FU bolus5-FU bolus
Compared to monthly bolus 5-FU/LV: same efficacy: 73% 3-year DFS decreased toxicity
5-FU infusion5-FU infusion 5-FU infusion5-FU infusion
D1D1 5-FU bolus5-FU bolus D2D2
LV LV
5-FU bolus5-FU bolus
OXA
MOSAIC Rationale 3:MOSAIC Rationale 3:FOLFOX4 in FOLFOX4 in metastaticmetastatic coloreactal cancer coloreactal cancer
Improved PFS compared to:
LV5FU2 de Gramont et al. J Clin Oncol 2000
IFL Goldberg et al. J Clin Oncol 2004
LV
OXA
R
MOSAIC: Treatment arms
*ambulatory infusion
LV5FU2
FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²
Every 2 weeks, 6 months of treatment (12 cycles)
D1D1 5-FU bolus5-FU bolus D2D2 5-FU bolus5-FU bolus
LV LV5-FU infusion* 5-FU infusion*
D1D1 5-FU bolus5-FU bolus D2D2 5-FU bolus5-FU bolus
LV LV5-FU infusion* 5-FU infusion*
MOSAIC: Patient characteristics
FOLFOX4 LV5FU2 (n=1123) (n=1123)
Median age, years 61 60
Male/Female % 56 /44 52 /48
KPS 80-100 % 86.2 87.6
Stage II/ III % 40 /60 40 /60
Bowel obstruction % 18 19
Perforation % 7 7Stratification for TNM stage, bowel obstruction/perforation, center
Median time surgery – start chemo: 5.7 wks (range 1.1 – 17)
DFS by treatment arm (ITT)
0,5
0,6
0,7
0,8
0,9
1
0 10 20 30 40 50 months
Probability
Hazard ratio: 0.76 [0.64 – 0.89] p =0.0008
24% risk reduction in the FOLFOX4 arm
3-year DFS
FOLFOX4 (n=1123) 78.7%LV5FU2 (n=1123) 73.3%
abs. difference = 5.4%
Disease-Free Survival Stage III patients
0,5
0,6
0,7
0,8
0,9
1
0 10 20 30 40 50
Probability
months
25% risk reduction for stage III patients
Hazard ratio: 0.75 [0.62-0.90] p=0.002Hazard ratio: 0.75 [0.62-0.90] p=0.002
3-year DFS
FOLFOX4 (n=672) 72.8%LV5FU2 (n=675) 65.8%
abs. difference = 7.0%
Disease-Free Survival Stage II patients
0,5
0,6
0,7
0,8
0,9
1
0 10 20 30 40 50
Hazard ratio: 0.79 [0.57-1.09] p=0.151Hazard ratio: 0.79 [0.57-1.09] p=0.151
Probability
months
21% risk reduction for stage II patients
3-year DFS
FOLFOX4 (n=451) 87.4%LV5FU2 (n=448) 84.3%
abs. difference = 3.1%
DFS analysis according to prognostic factors
ITT population
MaleFemale> 65 years old< 65 years oldT4T1,T2,T3N2N0,N1Stage IIIStage IIBowel obstructionNo obstructionTumour perforationNo perforationBaseline CEA > 5Baseline CEA < 5Well/moderately differentiatedPoorly differentiatedVenous invasionNo venous invasion
FOLFOX better LV5FU2 better
MOSAIC: Safety results, toxicity per patient
NCI Gr 3 % FOLFOX4 LV5FU2 (n=1108) (n=1111)
Thrombocytopenia 1.7 0.4
Neutropenia 41.1 (Gr 4: 12.2) 4.7
Febrile neutropenia 0.7 0.1
Neutropenic sepsis 1.1 0.1
Diarrhoea 10.8 6.7
Stomatitis 2.7 2.2
Vomiting 5.9 1.4
Allergy 3.0 0.2
Alopecia (Gr 2) 5.0 5.0
All cause mortality 0.5 0.5
MOSAIC:Peripheral sensory neuropathy
Paresthesias FOLFOX4 arm
Per patient One year(n=1108) after
Grade 0 8 % 70 %
Grade 1 48.1 % 24 %
Grade 2 31.5 % 5 %
Grade 3 12.4 % 1 %
Overall 82% 30%
(NCI version 1)
High-risk stage II colon cancer
Either of the following characteristics:
•Stage T4
• < 10 regional lymphnodes examined
•Bowel obstruction
• Tumor perforation
•Poorly differentiated histology
•Venous invasion
MOSAIC study in stage II/III colon cancer
Patients (n) 5FU/LV FOLFOX
total 1123 1123
Stage III 675 (60%) 672 (60%)
Stage II 448 (40%) 451 (40%)
High-risk stage II 290 (26%) 286 (25%)
Hickish et al. ASCO/ESMO 2004
0 6 12 18 24 30 36 42 48
3-year DFSFOLFOX4 (n=286) 84.9%LV5FU2 (n=290) 79.8%
abs. difference 5.1%
28% risk reduction in the FOLFOX4 arm
1.01.0
0.90.9
0.80.8
0.70.7
0.60.6
months
Probability
Disease-Free Survival High-risk stage II patients
Disease-Free Survival High-risk stage II patients
Hazard ratio 0.72 [0.48-1.08] N.S.
MOSAIC study in subgroups of colon cancer
Hazard ratio for relapse (95% CI)
Decrease in relative risk
of recurrence
Absolute difference in
3-yr DFS
Overall
n = 2246
0.76
(0.64-0.89) p.0008
24% 5.4% #
Stage III
n = 1247
0.76
(0.62-0.92) p.002
25% 7.0%
Stage II
n = 899
0.80
(0.56-1.15) NS
21% 3.1%
High-risk stage II
n = 576
0.72
(0.48-1.08) NS
28% 5.1%
# 4-yr DFS 75.9% vs. 69.1%, abs. diff. 6.8%
FOLFOX as adjuvant treatment in colon cancer
•Significant DFS benefit overall (stage II + III)
•MOSAIC study not designed for stage II – III subgroups
•Significant benefit in stage III, overall increasing after longer follow-up (DFS 3yrs. 5.4% 4-yrs. 6.8%)
•With so many effective drugs available, overall survival as endpoint becomes less reliable
FOLFOX as adjuvant treatment in stage II colon cancer
•Benefit in stage II is small, non-significant
•Benefit in high-risk stage II seems comparable to stage III but non-significant (underpowered)
•Prospective studies in high-risk stage II will probably never be performed
FOLFOX as adjuvant treatment in stage II colon cancer
•Relapse rate in stage II 20%
•Absolute benefit of 5FU/LV 4%
To cure 1 patient, 25 patients have to be treated
•Additional benefit of FOLFOX 3% (extrapolation!)
To cure 1 patient, 14 patients have to be treated
One out of 25 overall will not relapse if treated by FOLFOX instead of 5FU/LV
Proposal for new standard adjuvant treatment in stage III colon cancer
• FOLFOX 12 cycles q 2 weeks
• For patients refusing or ineligible for FOLFOX: capecitabine 8 cycles q 3 weeks
•Capecitabine + oxaliplatin should not be administered outside adjuvant trials (ongoing)
Proposal for new standard adjuvant treatment in stage II colon cancer
Stage II overall
• capecitabine 8 cycles q 3 weeks, or observation ?
Stage II high-risk:
• FOLFOX or capecitabine ?
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