Clinical prognostic factorsClinical prognostic factors

Claus-Henning Köhne

Klinik für Onkologie und Hämatologie

ESMO

21. September 2009

Berlin

Germany

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

Survival according to liver resections

Kopetz et al. JCO 2009

The Problem

Seperate those patients who need upfront combination therapy from

those who do not

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

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

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

Choices in MCRC

Strategy Curative palliative

Therapy Chemotherapy Biologicals

upfront combination sequential

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

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

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%

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%

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

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)

The Hypothesis

Clinical prognostic factors may help identifying patients who need or do not need upfront

therapy

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

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)

„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

Prognostic variablesPrognostic variables

„How do you do?“

Ask about appetite

Determine PS

Check weight

Loprinzi JCO 1994

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

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

(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

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

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 ?

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

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

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

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

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

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

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

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