clinical prognostic factors claus-henning köhne klinik für onkologie und hämatologie esmo 21....
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Clinical prognostic factorsClinical prognostic factors
Claus-Henning Köhne
Klinik für Onkologie und Hämatologie
ESMO
21. September 2009
Berlin
Germany
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Survival of patient with metastatic CRC over decadesCensored for patients with liver resection
Survival of patient with metastatic CRC over decadesCensored for patients with liver resection
Kopetz et al. JCO 2009
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Survival according to liver resections
Kopetz et al. JCO 2009
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The Problem
Seperate those patients who need upfront combination therapy from
those who do not
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Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients
Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients
OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85Grothey & Sargent, JCO 2005
0 10 20 30 40 50 60 70 80
Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV
LV5FU2
22
21
20
19
18
17
16
15
14
13
12
Med
ian
OS
(m
o)
Patients with 3 drugs (%)
P =.0001
First-Line Therapy
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6
Survival following 5-FU based treatments
TTP survival Total Survivalafter x-line
1st line 5 mo 13 mo 13 mo(#386)
2nd line 4 mo 9 mo 19 mo(#182)
3rd line 3 mo 7 mo 24 mo(#80)
4th line 3 mo 6 mo 27 mo(#33)
Köhne et al ASCO 98
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Drugs beyond progression to 1st line treatmentDrugs beyond progression to 1st line treatment
Grothey et al. JCO 2008 Kopetz et al. JCO 2008
Bevacizumab Ondansetron
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Choices in MCRC
Strategy Curative palliative
Therapy Chemotherapy Biologicals
upfront combination sequential
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0 6 12 18 24 30 36
Time t (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
bab
ilit
y of
Su
rviv
ing
Tim
e
t
50 %
20 %
CR/PR PD: 10%
PD: 30%
Effect of Response Rates on Total Survival(Estimation by mathematical model)
Shoulder effectShoulder effect
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0 6 12 18 24 30 36
Time t (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
bab
ilit
y of
Su
rviv
ing
Tim
e
t
CR/PR PD 2nd line
50 % 20 % 0 %
20 % 30 % 100 %
20 % 30 % 0 %
Effect of Response Rates and 2nd line therapy on Total Survival (Estimation by mathematical model)
Tail effectTail effect
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LV5FU2 vs. LV5FU2 + Oxaliplatin
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40
Survival
p=0.11
DeGramont et al. JCO 2000
RR PD 2nd CPT-11 L-OHP
LV5FU2 22% 16% 61% 20% 37% +/- L-OHP 51% 10% 58% 30% 30%
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5-FU/FA +/- CPT-11
Douillard et al. Lancet 2000
RR PD 2nd CPT-11 L-OHP
FUinf/FA 23% 26% 65% 34% 16% +/- CPT-11 35% 19% 49% 11% 13%
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Studies investigating sequential tretamentStudies investigating sequential tretamentStudies investigating sequential tretamentStudies investigating sequential tretament
FOCUS
N=2100
5FU Iri CapOx5FU FOLFIRI CapOx5FU FOLFOX CapIriFOLFOX CapIriFOLFIRI CapOx
CAIRO
N=803
Cape CapIri CapOxCapIri CapOx
LIFE
N=725
5FU CapOx IriCapeOx Iri
Pluzanska et al., ASCO 2005; Seymour et al., Lancet 2007; Koopman et al., Lancet 2007
End point
OS
End point
OS
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LIFE, FOCUS und CAIRO: N = 3663 LIFE, FOCUS und CAIRO: N = 3663 No benefit for „upfront combination“ No benefit for „upfront combination“ LIFE, FOCUS und CAIRO: N = 3663 LIFE, FOCUS und CAIRO: N = 3663
No benefit for „upfront combination“ No benefit for „upfront combination“
Cunningham et al., Ann Oncol 2009; Seymour et al., Lancet 2007; Koopman et al., Lancet 2007
15.215.2
15.915.9
15.215.2
15.915.9
16.316.3
17.417.4
16.316.3
17.417.4
15.315.3
16.316.3
15.315.3
16.316.3
However:
Most patients were PS 0/1 (96% CAIRO) and / or potentially resectable excluded (FOCUS)
Do subgroups benefit from 1st line combination?
Combination treatment remains therapy of choice (Schmoll/Sargent Lancet 2007)
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The Hypothesis
Clinical prognostic factors may help identifying patients who need or do not need upfront
therapy
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Influence of TNM stage on prognosisTime from Recurrence to Death by Stage
Log Rank P-Value = <0.0001
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8Time (Years)
% A
live
Stage II (N=1153)
Stage III (N=4550)
Total (N=5703)
O‘Connel et al JCO 2008
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Time from Recurrence to Death byAdjuvant Treatment vs. Surgery Alone
Log Rank P-Value = 0.0005
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
Time (Years)
% A
live
Surgery Alone (N=916)
Adjuvant Treatment (N=754)
Total (N=1670)
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„Old fashioned“ Performance Status„Old fashioned“ Performance Status
Karnofsky score introduced 1949
KPS (10 scale) correllates well with ECOG (5
scale)
High inter-observer agreement (Vincent Cancer 1984)
Strong prognostic information
Karnofsky score introduced 1949
KPS (10 scale) correllates well with ECOG (5
scale)
High inter-observer agreement (Vincent Cancer 1984)
Strong prognostic information
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Prognostic variablesPrognostic variables
„How do you do?“
Ask about appetite
Determine PS
Check weight
Loprinzi JCO 1994
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Subgroup analysis in FOCUS and CAIRO
Combination better
FOCUS HR p-value
PS 2 1.44 0.063
> WBC 1.27 0.003
CAIRO PS 2 1.44 0.04
> LDH 1.9 0.0001
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CM923700-21
OS – Infusional Combo by PSOS – Infusional Combo by PSSargent, Köhne et al. JCO 2009Sargent, Köhne et al. JCO 2009
OS – Infusional Combo by PSOS – Infusional Combo by PSSargent, Köhne et al. JCO 2009Sargent, Köhne et al. JCO 2009
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30
Months
% A
live
Other ~ PS 0-1 (median = 15.5 mos)
Infusional Combo ~ PS 0-1 (median = 18.8 mos)
Other ~ PS 2 (median = 6.4 mos)
Infusional Combo ~ PS 2 (median = 11.8 mos)
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30
Months
% A
live
Other ~ PS 0-1 (median = 15.5 mos)
Infusional Combo ~ PS 0-1 (median = 18.8 mos)
Other ~ PS 2 (median = 6.4 mos)
Infusional Combo ~ PS 2 (median = 11.8 mos)
p-value < 0.0001
HR: 0.84 (0.78-0.91)p-value < 0.0001
HR: 0.69 (0.54-0.88)
Interaction p-value = 0.004
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(534)
Total Survival General Prediction Model
3 Risk groups
Total Survival General Prediction Model
3 Risk groups
>1 0, 1
< 10 x109/l > 1 1
1> 1
146 1111
180755
(1111)(962)
No. ofpatients
149208
ECOG 2549
N of Sites 357
Split variable
Higher riskcriterion
Lower riskcriterion
WBC 503
N of Sites 2046
AP 935
>300 U/L
Median Learning set: 6.1 (5.6 - 6.8) 10.7 (10.2 – 11.4) 15.0 (13.9 – 15.8)
(95% C.I.) Validation set: 6.4 (5.7 – 7.2) 10.9 (9.9 – 11.9) 14.7 (13.5– 15.8)
> 10 x109/l
<300 U/L
Köh
ne e
t al.
An
n O
ncol 2002
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0 12 24 36 48 60 72 84
Months
0.00
0.25
0.50
0.75
1.00
Cu
mu
lati
ve S
urv
ival
Group: Learning Validation
N Pat 2549 1276
Kaplan-Meier
95 % C.I.
Median
Good risk: 15.0 Mo 14.7 Mo
intermediate risk: 10.7 Mo 10.9 Mo
Poor risk: 6.1 Mo 6.4 Mo
Group: Learning Validation
N Pat 2549 1276
Kaplan-Meier
95 % C.I.
Median
Good risk: 15.0 Mo 14.7 Mo
intermediate risk: 10.7 Mo 10.9 Mo
Poor risk: 6.1 Mo 6.4 Mo
Survival according to risk groups : Learning and Validation set
Köhne & Hecker JCO submitted
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Limitations of the modelLimitations of the model
Clinical trials published during 1990‘s Fluoropyrimidine alone No irinotecan or oxaliplatin No EGFR‘s or VEGF inhibitors
Does this model have importance for newer therapies ?
Clinical trials published during 1990‘s Fluoropyrimidine alone No irinotecan or oxaliplatin No EGFR‘s or VEGF inhibitors
Does this model have importance for newer therapies ?
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Prognostic groups with irinotecan or oxaliplatin combination treatment
Prognostic groups with irinotecan or oxaliplatin combination treatment
Oxaliplatin und Irinotecan containg regimens
Risk N=1691 N=142
low 20.8 20.0
Interm. 17.4 15.7
poor 9.4 6.8
Sanoff et al. Diaz-R et a.
JCO 2008 Clin Colo Can 2005
Oxaliplatin und Irinotecan containg regimens
Risk N=1691 N=142
low 20.8 20.0
Interm. 17.4 15.7
poor 9.4 6.8
Sanoff et al. Diaz-R et a.
JCO 2008 Clin Colo Can 2005
Sanoff et al. JCO 2008
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Implications of prognostic modelClinical trials: Parameters that must be reported
Implications of prognostic modelClinical trials: Parameters that must be reported
Age median
Gender
PS PS 0/1 vs. 2
Site of primary
Surgery of primary tumor
Prior adjuvant chemotherapy
Prior radiotherapy
Metastatic sites 1 vs. >1
Alkaline phophatase > UNL
WBC > 10x109/l
Age median
Gender
PS PS 0/1 vs. 2
Site of primary
Surgery of primary tumor
Prior adjuvant chemotherapy
Prior radiotherapy
Metastatic sites 1 vs. >1
Alkaline phophatase > UNL
WBC > 10x109/l
Sorbye et al. Ann Oncol 2007
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Patients < 70 years
Overall survival (months)
60483624120
100%
80%
60%
40%
20%
0%
infusional
5-FU
Bolus-
5-FU
Patients >= 70 years
Overall survival (months)
60483624120
100%
80%
60%
40%
20%
0%
infusional
5-FU
Bolus-
5-FU
Overall survival and 5-FU administration Overall survival and 5-FU administration
Patients < 70 y. Patients >= 70 y.
mo (95% CI) mo (95% CI)
inf. FU 12.3 (11.5-13.2) 11.9 (9.4-14.5)
bol.FU 10.7 (10.3-11.2) 11.3 (9.0-11.5)
p < 0.0001 p = 0.014
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0 6 12 18 24 30 36 42 48
Overall Survival (months)
0,0
0,2
0,4
0,6
0,8
1,0
Ku
m. Ü
berl
eb
en
Treatment groups5-FU bolus
5-FU bolus + irinotecan
5-FU infus
5-FU infus + irinotecan
5-FU bolus + irinotecan-zensiert
5-FU bolus -zensiert
5-FU infus + irinotecan-zensiert
5-FU infus-zensiert
pAge = < 70
Überlebensfunktionen
0 6 12 18 24 30 36 42 48
Overall Survival (months)
0,0
0,2
0,4
0,6
0,8
1,0
Ku
m.
Üb
erl
eb
en
Treatment groups5-FU bolus
5-FU bolus + irinotecan
5-FU infus
5-FU infus + irinotecan
5-FU bolus + irinotecan-zensiert
5-FU bolus -zensiert
5-FU infus + irinotecan-zensiert
5-FU infus-zensiert
pAge = >= 70
Überlebensfunktionen
< 70 years n=2092 ≥ 70 years n=599
── 5-FU infus. / Iri
- - - 5-FU bolus / Iri
── 5-FU infus.
- - - 5-FU bolus
FOLFIRI 1st line
Overall survival depending on age and 5-FU schedule
in 2,691 patients, 4 studies
treated with
5-FU +/- irinotecan
Folprecht….Köhne et al, JCO 2008
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0
10
20
30
40
50
60
70
80
90
100
0 1 2
Years
% A
liv
e
FOLFOXControl
HR=0.73
0
10
20
30
40
50
60
70
80
90
100
0 1 2Years
% A
liv
e
FOLFOXControl
HR=0.67
Age < 70 Age > 70
OS - First line de Gramont, Goldberg Studies
Goldberg et al. JCO 2006
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ConclusionsConclusions Stage II and stage III colon cancer are most likely
two different diseases Relaps following adjuvant chemotherapy selects an
unfavorable subgroup Clinical prognostic parameters are powerful tools Poor risk patients need upfront combination
therapy Sequential approach is an option for intermediate
and good risk patients
Stage II and stage III colon cancer are most likely two different diseases
Relaps following adjuvant chemotherapy selects an unfavorable subgroup
Clinical prognostic parameters are powerful tools Poor risk patients need upfront combination
therapy Sequential approach is an option for intermediate
and good risk patients
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ConclusionsConclusions
Patient groups Therapy
~15% curative potential combination CTx
~15% PS 2 or combination CTx
poor risk factors
~70% intermediate or sequential approach
good risk possible
Patient groups Therapy
~15% curative potential combination CTx
~15% PS 2 or combination CTx
poor risk factors
~70% intermediate or sequential approach
good risk possible
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Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients
Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients
OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85Grothey & Sargent, JCO 2005
0 10 20 30 40 50 60 70 80
Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV
LV5FU2
22
21
20
19
18
17
16
15
14
13
12
Med
ian
OS
(m
o)
Patients with 3 drugs (%)
P =.0001
First-Line Therapy
FOFOXIRI 1st line