Transcript Adjuvante therapie van het coloncarcinoom anno 2004

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
Nijmegen
Adjuvant therapy for colon cancer
hot 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
Saltz et al. ASCO 2004
Data are accumulating that irinotecan should be
combined with infusional and not bolus 5FU
Primary endpoint in
randomised adjuvant studies
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
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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 !!
Adjuvant treatment
in stage II colon cancer
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
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•
1
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
2 studies without observation arm
2 stage II and stage III colon+rectal
Adjuvant treatment in stage II colorectal
cancer – QUASAR study
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
Gray et al. ASCO 2004
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%
Oral fluoropyrimidines
as adjuvant treatment
for colon cancer
UFT/LV versus 5FU/LV (Roswell Park schedule)
in stage II + III colon cancer
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
Wolmark et al. ASCO 2004
X-ACT trial in adjuvant treatment
of stage III colon cancer
Capecitabine
1 250 mg/m2 twice daily,
d1–14, q21d
n=1 004
Stage III
resection <8 weeks
24 weeks
Bolus 5-FU/LV
5-FU 425 mg/m2 plus
LV 20 mg/m2, d1–5, q28d
n=983
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•
1° endpoint: DFS
2° endpoints
• OS
• tolerability
• pharmacoeconomics
• QoL
X-ACT powered to establish at least
equivalence of capecitabine to 5-FU/LV
• Primary endpoint DFS


80% power for at least equivalence
primary endpoint met if upper limit 95% CI HR <1.25
• Secondary analyses



tests for superiority
RFS, OS
multivariate 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) (%)
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
Age, median (range)
Cassidy et al. ASCO 2004
DFS: primary endpoint achieved (ITT)
Estimated probability
1.0
Capecitabine (n=1004)
5-FU/LV (n=983)
0.8
0.6
HR = 0.87 (95% CI: 0.75–1.00)
0.4
0
1
2
3
Years
4
5
6
Capecitabine showed trend to
superior DFS (ITT)
Estimated probability
3-year DFS
1.0
Capecitabine (n=1004)
64.2%
5-FU/LV (n=983)
60.6%
0.8
0.6
p=0.0528
Absolute difference
at 3 years: 3.6%
0.4
0
1
2
3
Years
4
5
6
Capecitabine showed trend to
improved OS (ITT)
Estimated probability
1.0
3-year OS
Capecitabine (n=1004)
81.3%
5-FU/LV (n=983)
77.6%
0.8
Absolute difference
at 3 years: 3.7%
0.6
HR = 0.84 (95% CI: 0.69–1.01)
p=0.0706
0.4
0
1
2
3
Years
4
5
6
Capecitabine consistent benefit in
subgroup analysis for DFS
capecitabine better Bolus 5-FU/LV better
n
ITT population
1987
Male
Female
1074
912
<40
40–69 years old
≥70
76
1543
396
N1 (1–3 nodes)
N2 (4 nodes)
1389
593
Baseline CEA <ULN 1672
Baseline CEA >ULN 155
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8 Hazard ratio and 95% CI
Fewer key grade 3/4 toxicities and
later onset with capecitabine
Estimated probability of grade 3/4 adverse event
1.0
5-FU/LV
capecitabine
0.8
0.6
p<0.001
0.4
0.2
0
0
1
2
3
4
5
6
7
Months
Grade 3/4 diarrhoea, stomatitis, nausea, vomiting, alopecia,
hand-foot syndrome, neutropenia
8
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
FOLFOX
as adjuvant treatment
for colon cancer
MOSAIC: Study Design
stage II + III colon cancer
FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²
R
LV5FU2
Endpoints

Primary:
– Disease-Free Survival (DFS)

Secondary:
– Safety (including long-term)
– Overall Survival (OS)
MOSAIC Rationale 1:
LV5FU2 in metastatic colon cancer
D1 5-FU bolus
LV
5-FU infusion
D2 5-FU bolus
LV
5-FU infusion
Compared to monthly bolus 5-FU/LV:
 improved progression-free survival
 decreased toxicity
de Gramont et al. J Clin Oncol, 1997
MOSAIC Rationale 2:
LV5FU2 in adjuvant colon cancer
D1 5-FU bolus
LV
5-FU infusion
D2 5-FU bolus
LV
5-FU infusion
Compared to monthly bolus 5-FU/LV:
 same efficacy: 73% 3-year DFS
 decreased toxicity
André et al. J Clin Oncol, 2003
MOSAIC Rationale 3:
FOLFOX4 in metastatic coloreactal cancer
D1 5-FU bolus
LV
D2 5-FU bolus
5-FU infusion
LV
5-FU infusion
OXA
Improved PFS compared to:
 LV5FU2
 IFL
de Gramont et al. J Clin Oncol 2000
Goldberg et al. J Clin Oncol 2004
MOSAIC: Treatment arms
FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²
D1 5-FU bolus
LV
5-FU infusion*
D2 5-FU bolus
LV
LV
5-FU infusion*
OXA
R
D1 5-FU bolus
LV5FU2
LV
5-FU infusion*
D2 5-FU bolus
LV
5-FU infusion*
Every 2 weeks, 6 months of treatment (12 cycles)
*ambulatory infusion
MOSAIC: Patient characteristics
FOLFOX4
(n=1123)
Median age, years
Male/Female %
LV5FU2
(n=1123)
61
56 /44
60
52 /48
86.2
87.6
40 /60
40 /60
Bowel obstruction %
18
19
Perforation %
7
7
KPS 80-100 %
Stage II/ III %
Stratification for TNM stage, bowel obstruction/perforation, center
Median time surgery – start chemo: 5.7 wks (range 1.1 – 17)
DFS by treatment arm (ITT)
3-year DFS
Probability
1
FOLFOX4 (n=1123)
78.7%
LV5FU2 (n=1123)
73.3%
abs. difference = 5.4%
0,9
0,8
0,7
0,6
Hazard ratio: 0.76 [0.64 – 0.89]
p =0.0008
0,5
0
10
20
30
40
50 months
24% risk reduction in the FOLFOX4 arm
Probability
1
Disease-Free Survival
Stage III patients
3-year DFS
FOLFOX4 (n=672)
72.8%
LV5FU2 (n=675)
65.8%
abs. difference = 7.0%
0,9
0,8
0,7
0,6
Hazard ratio: 0.75 [0.62-0.90] p=0.002
0,5
0
10
20
30
40
50 months
25% risk reduction for stage III patients
Probability
Disease-Free Survival
Stage II patients
1
0,9
3-year DFS
0,8
FOLFOX4 (n=451)
87.4%
LV5FU2 (n=448)
84.3%
abs. difference = 3.1%
0,7
0,6
Hazard ratio: 0.79 [0.57-1.09] p=0.151
0,5
0
10
20
30
40
50 months
21% risk reduction for stage II patients
DFS analysis according to prognostic factors
ITT population
Male
Female
> 65 years old
< 65 years old
T4
T1,T2,T3
N2
N0,N1
Stage III
Stage II
Bowel obstruction
No obstruction
Tumour perforation
No perforation
Baseline CEA > 5
Baseline CEA < 5
Well/moderately differentiated
Poorly differentiated
Venous invasion
No venous invasion
FOLFOX better
LV5FU2 better
MOSAIC: Safety results, toxicity per patient
NCI  Gr 3
%
Thrombocytopenia
Neutropenia
FOLFOX4
LV5FU2
(n=1108)
(n=1111)
1.7
0.4
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
(NCI version 1)
FOLFOX4 arm
Per patient
(n=1108)
One year
after
Grade 0
8%
70 %
Grade 1
48.1 %
24 %
Grade 2
31.5 %
5%
Grade 3
12.4 %
1%
Overall
82%
30%
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
1123
1123
Stage III
675 (60%)
672 (60%)
Stage II
448 (40%)
451 (40%)
High-risk stage II
290 (26%)
286 (25%)
total
Hickish et al. ASCO/ESMO 2004
Disease-Free Survival
High-risk stage II patients
3-year DFS
FOLFOX4 (n=286)
84.9%
LV5FU2 (n=290)
79.8%
Probability
1.0
abs. difference 5.1%
0.9
0.8
0.7
Hazard ratio 0.72 [0.48-1.08] N.S.
28% risk reduction in the FOLFOX4 arm
0.6
0
6
12
18
24
30
36
42
48 months
MOSAIC study in subgroups of colon cancer
Hazard ratio for
relapse (95% CI)
Decrease in
Absolute
relative risk difference in
of recurrence
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
New standards for adjuvant
treatment in stage II and III
colon cancer
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 ?
•
Adjuvant treatment in colon cancer:
which option is best for our patients?
• patients must be informed about:
 the reality of treatment
 the associated risks/benefits
• Information should be provided by a physician with
experience in chemotherapy