Therapie des Kolonkarzinoms Trendwende dank neuer Medikamente

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1 Therapie des Kolonkarzinoms Trendwende dank neuer Medikamente Prof. Dr. Markus M. Borner Institut für Medizinische Onkologie Universität Bern, Inselspital

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3 Fluorouracil Zellteilung alle x Tage - Wochen TAG TCTT ATCCGTA Fluorouracil Halbwertszeit Minuten

4 Mittleres Ueberleben Chemotherapie v supportive Th 5.0 vs 11.0 Mo (.006) Scheithauer, BMJ, 1993, 752

5 Mittleres Ueberleben Fluorouracil ± Leucovorin 10.0 vs 12.4 Mo (.02) Borner M et al. Ann Oncol 1998, 535

6 Irinotecan (Campto )

7 Zusammenfassung Resultate Effektivität Fluorouracil / Leucovorin ± Irinotecan Regimen Response rate (%) PFS (months) Median survival (months) Bolus (USA) 1 Irinotecan/5-FU/LV 5-FU/LV 39* * * 12.6 Irinotecan Infused (Europe) 2 Irinotecan/5-FU/LV 5-FU/LV 35* * * 14.1 Combined data 3 Irinotecan/5-FU/LV 5-FU/LV 37* * * 13.3 *p<0.05 (vs 5-FU/LV) 1 Saltz LB et al. N Engl J Med 2000;343: Douillard JY et al. Lancet 2000;355: Saltz LB et al. Proc Am Soc Clin Oncol 2000;19:242a (Abst 938)

8 Oxaliplatin (Eloxatin ) G N G Oxaliplatin

9 Phase III Studien Erstlinientherapie mit Fluorouracil / Leucovorin ± Oxaliplatin Response rate (%) Median PFS (months) Median overall survival (months) 5-FU/LV FU/LV + Oxaliplatin 50* 9.0* 16.2 *p<0.001 de Gramont A et al. J Clin Oncol 2000;18:

10 Womit beginnen? Irinotecan vs Oxaliplatin Crossover Campto zuerst Oxaliplatin zuerst OS 21.5 mo 20.6 mo TTP1 TTP2 RR1 RR2 8.5 mo 14.2 mo 56% 15% 8.0 mo 10.9 mo 54% 4% Tournigand et al. J Clin Oncol, 229, 2004

11 mehr Medikamente längeres Ueberleben Grothey et al. J Clin Oncol 2004, 1209

12 Standardchemotherapie Metastasierendes Kolonkarzinom Chemotherapie: 1. Linie Oxaliplatin 5-FU Irinotecan Chemotherapie: 2. Linie Oxaliplatin 5-FU Irinotecan

13 Molekulare Therapie Proliferation Gefässneubildung Zelltod (Apoptose) Karzinom

14 Hemmung der Angiogenese Bevacizumab (Avastin ) Angiogene Faktoren Gefäss- Knospe VEGF extrazelluläre Matrix EZM Degradation Tumor- Wachstum VEGF = Vascular Endothelial Growth Factor

15 Chemotherapy ± Bevacizumab Phase III Studie No bevacizumab past disease progression Metastasierendes Kolonkarzinom nicht vorbehandelt Bolus IFL + Placebo (n=411) Bolus IFL + Bevacizumab (n=402) 5-FU/LV + bevacizumab (n=110) IFL: Irinotecan Fluorouracil Leucovorin Bevacizumab: 5mg/kg alle 2 Wochen Hurwitz H, et al. N Engl J Med Jun 3;350(23):

16 Irinotecan/FU/LV ± Bevacizumab Response rate Overall Complete Partial Phase III Studie IFL + placebo (n=411) IFL + bevacizumab (n=402) p versus placebo Response duration (months) Hazard ratio Survival (months) Progression-free survival (months) < Hurwitz H, et al. N Engl J Med Jun 3;350(23):

17 Survival 1.0 Probability of survival IFL + placebo IFL + bevacizumab Hazard ratio = 0.66, p= Median survival 15.6 (IFL + placebo) vs 20.3 months (IFL + bevacizumab) Survival (months)

18 Fluorouracil/LV ± Bevacizumab Phase III Studie Kabbinavar, JCO 2005, 3706

19 Zweitlinientherapie Oxaliplatin ± Bevacizumab Previously treated metastatic CRC FOLFOX4 + bevacizumab (10mg/kg, q2 weeks) FOLFOX4 PD PD Bevacizumab (10mg/kg, q2 weeks) PD PS = performance status FOLFOX = 5-fluorouracil (5-FU)/leucovorin (LV) + oxaliplatin PD = progression of disease XRT = radiotherapy Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)

20 Bevacizumab Bevacizumab in in der der Linie Linie 1.0 Probability 0.8 HR= A vs B: p< B vs C: p< Progression-free survival (months) A: FOLFOX4 + bevacizumab B: FOLFOX4 C: Bevacizumab Total Fail Cens Median Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)

21 Bevacizumab in der Standardtherapie des Kolonkarzinoms Chemotherapie: 1. Linie Anti-VEGF 5-FU Irinotecan Chemotherapie: 2. Linie Anti-VEGF 5-FU Oxaliplatin

22 Epidermal Growth Factor Receptor (EGF-R) R R CELL MEMBRANE PTEN Akt PI3K K K Shc Sos Grb2 Ras Raf Signal Transduction GSK-3 mtor FKHR Bad NF-κβ MEK1/2 p27 MAPK Transkription NUCLEUS Zelluläre Funktionen Zellteilung Survivalsignale Angiogenese Metastasierung

23 EGF-R Expression in soliden Tumoren Kolorektal Lunge (NSCLC) HNO Kolorektal NSCLC HNO Mammakarzinom Ovalialkarzinom Nierenzellkarzinom 72-86% 40-91% % 14-91% 35-70% 50-90%

24 EGF-R Antikörper Cetuximab (Erbitux ) variable Region konstante Region Chimärer Antikörper gegen EGF-R (epidermal growth factor Rezeptor) hemmt Wachstum stimuliert zelluläre Immunantwort additive Wirkung mit Chemotherapie auch bei Chemotherapieresistenz Cetuximab

25 BOND Studie 329 patients with CRC progressed on or within 3 months of irinotecan-based chemotherapy 2:1 RANDOMIZATION irinotecan* * + cetuximab** n = 218 cetuximab** n = 111 on disease progression irinotecan* * + cetuximab** n = 56 Cunningham et al. Proc ASCO 2003, 1012

26 Ansprechen cetuximab + irinotecan (n=218) [49-62] ** Percentage [18-29] * 11 [6-18] 32 [24-42] 0 Response Rate * p=0.0074; ** p<0.001; [] = 95% CI Endpoint Disease Control (CR+PR+SD)

27 Nebenwirkungen

28 Hauttoxizität und Ueberleben Skin reaction none any grade 2 Acneiform rash none any grade 2 Combination Response (%) Survival (months) Monotherapy Survival rate (%) Survival (month)

29 Standardtherapie Metastasierendes Kolonkarzinom Chemotherapie: 1. Linie Anti-VEGF 5-FU Irinotecan Anti-VEGF Chemotherapie: 2. Linie 5-FU Oxaliplatin Anti-EGFR Chemotherapie: 3. Linie 5-FU Irinotecan

30 Neoadjuvante Therapie von Lebermetastasen Metastasen auf Leber beschränkt (30%) Leberresektion (10-20%) 30-40% geheilt inoperabel kaum Langzeitüberleben

31 Lebermetastasenchirurgie Survival (%) % 66% 52% 48% Resectable: 335 Initially non-resectable: % 20 p= % 23% Years Adam, et al. Ann Surg 2004;240:

32 Ansprechrate - Resektionsrate Resection rate,6,5,4 Studies including selected patients (liver metastases only, no extrahepatic disease) (r=0.96, p=0.002),3,2,1 Studies including all patients with mcrc (solid line) (r=0.74, p=0.001) 0,0,3,4,5,6,7,8,9 Phase III studies in mcrc (dashed line) (r=0.67, p=0.024) Response rate Folprecht G et al. Ann Oncol (2005)

33 Therapieoptionen RR % median survival:mos BSC 5FU FU/LV Cape CIFU IFL FOLFOX FOLFIRI FOLFOX IFL+B

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