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Clinical prognostic factors

ESMO 21. September 2009 Berlin Germany. Clinical prognostic factors. Claus-Henning Köhne Klinik für Onkologie und Hämatologie. Survival of patient with metastatic CRC over decades Censored for patients with liver resection. Kopetz et al. JCO 2009.

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Clinical prognostic factors

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

  2. Survivalofpatientwithmetastatic CRC overdecadesCensoredforpatientswithliverresection 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 200511 Phase III Trials, 5768 Patients 22 21 20 19 18 17 16 15 14 13 12 First-Line Therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2 Median OS (mo) P =.0001 0 10 20 30 40 50 60 70 80 Patients with 3 drugs (%) OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85 Grothey & Sargent, JCO 2005

  6. Survival following 5-FU based treatments TTP survival Total Survival after 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

  7. Drugs beyondprogressionto 1stlinetreatment Bevacizumab Ondansetron Grothey et al. JCO 2008 Kopetz et al. JCO 2008

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

  9. Effect of Response Rates on Total Survival (Estimation by mathematical model) 1.0 CR/PR PD: 10% 0.9 PD: 30% 50 % 0.8 20 % 0.7 0.6 Probability of Surviving Time t 0.5 0.4 0.3 Shoulder effect 0.2 0.1 0.0 0 6 12 18 24 30 36 Time t (months)

  10. Effect of Response Rates and 2nd line therapy on Total Survival (Estimation by mathematical model) 1.0 CR/PR PD 2nd line 0.9 50 % 20 % 0 % 20 % 30 % 100 % 0.8 20 % 30 % 0 % 0.7 0.6 Probability of Surviving Time t 0.5 0.4 0.3 Tail effect 0.2 0.1 0.0 0 6 12 18 24 30 36 Time t (months)

  11. LV5FU2 vs. LV5FU2 + Oxaliplatin Survival 100 RR PD 2nd CPT-11 L-OHP LV5FU2 22% 16% 61% 20% 37% +/- L-OHP 51% 10% 58% 30% 30% 90 80 70 60 50 40 30 20 p=0.11 10 0 0 10 20 30 40 DeGramont et al. JCO 2000

  12. 5-FU/FA +/- CPT-11 RR PD 2nd CPT-11 L-OHP FUinf/FA 23% 26% 65% 34% 16% +/- CPT-11 35% 19% 49% 11% 13% Douillard et al. Lancet 2000

  13. Studies investigatingsequentialtretament End point OS Pluzanska et al., ASCO 2005; Seymour et al., Lancet 2007; Koopman et al., Lancet 2007

  14. LIFE, FOCUS und CAIRO: N = 3663 No benefit for „upfront combination“ 15.2 15.9 15.3 16.3 16.3 17.4 However: Most patientswere PS 0/1 (96% CAIRO) and / orpotentiallyresectableexcluded (FOCUS) Do subgroupsbenefitfrom 1st linecombination? Combinationtreatmentremainstherapy of choice(Schmoll/Sargent Lancet 2007) Cunningham et al., Ann Oncol 2009; Seymour et al., Lancet 2007; Koopman et al., 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 100 Stage II (N=1153) Stage III (N=4550) Total (N=5703) 80 60 % Alive Log Rank P-Value = <0.0001 40 20 0 0 1 2 3 4 5 6 7 8 Time (Years) O‘Connel et al JCO 2008

  17. Time from Recurrence to Death by Adjuvant Treatment vs. Surgery Alone 100 Surgery Alone (N=916) Adjuvant Treatment (N=754) Total (N=1670) 80 60 % Alive 40 Log Rank P-Value = 0.0005 20 0 0 1 2 3 4 5 6 7 8 Time (Years)

  18. „Old fashioned“ Performance Status • Karnofsky score introduced 1949 • KPS (10 scale) correllates well with ECOG (5 scale) • High inter-observeragreement(Vincent Cancer 1984) • Strong prognosticinformation

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

  20. Subgroupanalysis 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

  21. OS – Infusional Combo by PSSargent, 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. Total Survival General Prediction Model 3 Risk groups Lower risk Higher risk No. of criterion criterion patients ECOG 2549 Split variable >1 0, 1 WBC503 N of Sites 2046 < 10 x109/l > 1 > 10 x109/l 1 Köhne et al. Ann Oncol 2002 AP 935 >300 U/L <300 U/L N of Sites 357 146 1111 1 > 1 149 755 180 208 (1111) (962) (534) 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)

  23. Survival according to risk groups : Learning and Validation set 1.00 Group: LearningValidation 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 0.75 0.50 Cumulative Survival 0.25 0.00 0 12 24 36 48 60 72 84 Köhne & Hecker JCO submitted Months

  24. Limitations of the model • Clinical trialspublishedduring 1990‘s • Fluoropyrimidinealone • Noirinotecanoroxaliplatin • NoEGFR‘sor VEGF inhibitors • Doesthis model haveimportancefornewertherapies ?

  25. PrognosticgroupswithirinotecanoroxaliplatincombinationtreatmentPrognosticgroupswithirinotecanoroxaliplatincombinationtreatment • Oxaliplatin und Irinotecancontaingregimens • 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 ClinColo Can 2005 Sanoff et al. JCO 2008

  26. Implications of prognostic modelClinical trials: Parameters that must bereported • Age median • Gender • PS PS 0/1 vs. 2 • Site of primary • Surgery of primarytumor • Prior adjuvantchemotherapy • Prior radiotherapy • Metastaticsites 1 vs. >1 • Alkalinephophatase > UNL • WBC > 10x109/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. 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

  28. FOLFIRI 1st line Overall survival depending on age and 5-FU schedule in 2,691 patients, 4 studies treated with 5-FU +/- irinotecan < 70 years n=2092 ≥ 70 years n=599 ── 5-FU infus. / Iri - - - 5-FU bolus / Iri ── 5-FU infus. - - - 5-FU bolus Folprecht….Köhne et al, JCO 2008

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

  30. Conclusions • Stage II andstage III coloncanceraremostlikelytwo different diseases • Relapsfollowingadjuvantchemotherapyselects an unfavorablesubgroup • Clinical prognosticparametersare powerful tools • Poor riskpatientsneedupfrontcombinationtherapy • Sequentialapproachis an optionfor intermediate andgoodriskpatients

  31. Conclusions • Patient groupsTherapy • ~15% curative potential combinationCTx • ~15% PS 2 orcombinationCTx • poorriskfactors • ~70% intermediate orsequentialapproach • goodriskpossible

  32. Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients FOFOXIRI 1st line 22 21 20 19 18 17 16 15 14 13 12 First-Line Therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2 Median OS (mo) P =.0001 0 10 20 30 40 50 60 70 80 Patients with 3 drugs (%) OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85 Grothey & Sargent, JCO 2005

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