1. Clinical prognostic factors Claus-Henning Köhne Klinik für Onkologie und Hämatologie ESMO 21. September 2009 Berlin Germany

2. Survival of patient with metastatic CRC over decades Censored for patients with liver resection Kopetz et al. JCO 2009

3. Survival according to liver resections Kopetz et al. JCO 2009

4. The Problem Seperate those patients who need upfront combination therapy from those who do not

5. Concept of “All-3-Drugs” - Update 2005 11 Phase III Trials, 5768 Patients OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85 Grothey & Sargent, JCO 2005 0 10 20 30 40 50 60 70 80 Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2 22 21 20 19 18 17 16 15 14 13 12 Median OS (mo) Patients with 3 drugs (%) P =.0001 First-Line Therapy

6. 6 Survival following 5-FU based treatments TTPsurvivalTotal Survival after x-line 1st line5 mo13 mo13 mo (#386) 2nd line4 mo9 mo19 mo (#182) 3rd line3 mo7 mo24 mo (#80) 4th line3 mo6 mo27 mo (#33) Köhne et al ASCO 98

7. Drugs beyond progression to 1 st line treatment Grothey et al. JCO 2008 Kopetz et al. JCO 2008 Bevacizumab Ondansetron

8. Choices in MCRC Strategy  Curative  palliative Therapy  Chemotherapy  Biologicals  upfront combination  sequential

9. 061218243036 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 Probability of Surviving Time t 50 % 20 % CR/PR PD: 10% PD: 30% Effect of Response Rates on Total Survival (Estimation by mathematical model) Shoulder effect

10. 061218243036 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 Probability of Surviving Time 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 effect

11. LV5FU2 vs. LV5FU2 + Oxaliplatin 0 10 20 30 40 50 60 70 80 90 100 010203040 Survival p=0.11 DeGramont et al. JCO 2000 RRPD2nd CPT-11L-OHP LV5FU222%16%61%20%37% +/- L-OHP51%10%58%30%30%

12. 5-FU/FA +/- CPT-11 Douillard et al. Lancet 2000 RRPD2nd CPT-11L-OHP FU inf /FA23%26%65%34%16% +/- CPT-1135%19%49%11%13%

13. Studies investigating sequential tretament FOCUS N=2100 5FUIriCapOx 5FUFOLFIRICapOx 5FUFOLFOXCapIri FOLFOXCapIri FOLFIRICapOx CAIRO N=803 CapeCapIriCapOx CapIriCapOx LIFE N=725 5FUCapOxIri CapeOxIri Pluzanska et al., ASCO 2005; Seymour et al., Lancet 2007; Koopman et al., Lancet 2007 End point OS End point OS

14. LIFE, FOCUS und CAIRO: N = 3663 No benefit for „upfront combination“ Cunningham et al., Ann Oncol 2009; Seymour et al., Lancet 2007; Koopman et al., Lancet 2007 15.215.915.215.9 16.317.416.317.4 15.316.315.316.3 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)

15. The Hypothesis Clinical prognostic factors may help identifying patients who need or do not need upfront therapy

16. Influence of TNM stage on prognosis Time from Recurrence to Death by Stage Log Rank P-Value = <0.0001 0 20 40 60 80 100 012345678 Time (Years) % Alive Stage II (N=1153) Stage III (N=4550) Total (N=5703) O‘Connel et al JCO 2008

17. Time from Recurrence to Death by Adjuvant Treatment vs. Surgery Alone Log Rank P-Value = 0.0005 0 20 40 60 80 100 012345678 Time (Years) % Alive Surgery Alone (N=916) Adjuvant Treatment (N=754) Total (N=1670)

18. „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

19. Prognostic variables „How do you do?“ Ask about appetite Determine PS Check weight Loprinzi JCO 1994

20. Subgroup analysis in FOCUS and CAIRO Combination better FOCUSHRp-value PS 21.440.063 > WBC1.270.003 CAIROPS 21.440.04 > LDH1.90.0001

21. CM923700-21 OS – Infusional Combo by PS Sargent, Köhne et al. JCO 2009 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

22. (534) Total Survival General Prediction Model 3 Risk groups >1 0, 1 < 10 x10 9 /l > 1 1 1 1461111 180 755 (1111) (962) No. of patients 149 208 ECOG 2549 N of Sites 357 Split variable Higher risk criterion Lower risk criterion 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 x10 9 /l <300 U/L Köhne et al. Ann Oncol 2002

23. 012243648607284 Months 0.00 0.25 0.50 0.75 1.00 Cumulative Survival 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

24. Limitations 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 ?

25. Prognostic groups with irinotecan or oxaliplatin combination treatment Oxaliplatin und Irinotecan containg regimens Risk N=1691N=142 low20.820.0 Interm.17.415.7 poor9.46.8 Sanoff et al.Diaz-R et a. JCO 2008Clin Colo Can 2005 Oxaliplatin und Irinotecan containg regimens Risk N=1691N=142 low20.820.0 Interm.17.415.7 poor9.46.8 Sanoff et al.Diaz-R et a. JCO 2008Clin Colo Can 2005 Sanoff et al. JCO 2008

26. Implications of prognostic model Clinical trials: Parameters that must be reported Agemedian Gender PSPS 0/1 vs. 2 Site of primary Surgery of primary tumor Prior adjuvant chemotherapy Prior radiotherapy Metastatic sites1 vs. >1 Alkaline phophatase> UNL WBC> 10x10 9 /l Agemedian Gender PSPS 0/1 vs. 2 Site of primary Surgery of primary tumor Prior adjuvant chemotherapy Prior radiotherapy Metastatic sites1 vs. >1 Alkaline phophatase> UNL WBC> 10x10 9 /l Sorbye et al. Ann Oncol 2007

27. Overall survival and 5-FU administration Patients < 70 y.Patients >= 70 y. mo(95% CI)mo(95% CI) inf. FU12.3(11.5-13.2) 11.9(9.4-14.5) bol.FU10.7(10.3-11.2) 11.3(9.0-11.5) p < 0.0001 p = 0.014

28. < 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

29. Age < 70Age > 70 OS - First line de Gramont, Goldberg Studies Goldberg et al. JCO 2006

30. Conclusions  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

31. Conclusions Patient groupsTherapy ~15%curative potential combination CTx ~15%PS 2 orcombination CTx poor risk factors ~70%intermediate orsequential approach good riskpossible Patient groupsTherapy ~15%curative potential combination CTx ~15%PS 2 orcombination CTx poor risk factors ~70%intermediate orsequential approach good riskpossible

32. Concept of “All-3-Drugs” - Update 2005 11 Phase III Trials, 5768 Patients OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85 Grothey & Sargent, JCO 2005 0 10 20 30 40 50 60 70 80 Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2 22 21 20 19 18 17 16 15 14 13 12 Median OS (mo) Patients with 3 drugs (%) P =.0001 First-Line Therapy FOFOXIRI 1st line