Therapie des Kolonkarzinoms Trendwende dank neuer Medikamente Prof. Dr. Markus M. Borner Institut für Medizinische Onkologie Universität Bern, Inselspital
Fluorouracil Zellteilung alle x Tage - Wochen TAG TCTT ATCCGTA Fluorouracil Halbwertszeit 20-30 Minuten
Mittleres Ueberleben Chemotherapie v supportive Th 5.0 vs 11.0 Mo (.006) Scheithauer, BMJ, 1993, 752
Mittleres Ueberleben Fluorouracil ± Leucovorin 10.0 vs 12.4 Mo (.02) Borner M et al. Ann Oncol 1998, 535
Irinotecan (Campto )
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* 21 7.0* 4.3 14.8* 12.6 Irinotecan 18 4.2 12.0 Infused (Europe) 2 Irinotecan/5-FU/LV 5-FU/LV 35* 22 6.7* 4.4 17.4* 14.1 Combined data 3 Irinotecan/5-FU/LV 5-FU/LV 37* 21 6.9* 4.3 15.9* 13.3 *p<0.05 (vs 5-FU/LV) 1 Saltz LB et al. N Engl J Med 2000;343:905 14 2 Douillard JY et al. Lancet 2000;355:1041 7 3 Saltz LB et al. Proc Am Soc Clin Oncol 2000;19:242a (Abst 938)
Oxaliplatin (Eloxatin ) G N G Oxaliplatin
Phase III Studien Erstlinientherapie mit Fluorouracil / Leucovorin ± Oxaliplatin Response rate (%) Median PFS (months) Median overall survival (months) 5-FU/LV 22 6.2 14.7 5-FU/LV + Oxaliplatin 50* 9.0* 16.2 *p<0.001 de Gramont A et al. J Clin Oncol 2000;18:2938 47
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
mehr Medikamente längeres Ueberleben Grothey et al. J Clin Oncol 2004, 1209
Standardchemotherapie Metastasierendes Kolonkarzinom Chemotherapie: 1. Linie Oxaliplatin 5-FU Irinotecan Chemotherapie: 2. Linie Oxaliplatin 5-FU Irinotecan
Molekulare Therapie Proliferation Gefässneubildung Zelltod (Apoptose) Karzinom
Hemmung der Angiogenese Bevacizumab (Avastin ) Angiogene Faktoren Gefäss- Knospe VEGF extrazelluläre Matrix EZM Degradation Tumor- Wachstum VEGF = Vascular Endothelial Growth Factor
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. 2004 Jun 3;350(23):2335-42.
Irinotecan/FU/LV ± Bevacizumab Response rate Overall Complete Partial Phase III Studie IFL + placebo (n=411) 34.8 2.2 32.6 IFL + bevacizumab (n=402) p versus placebo 44.8 3.7 41.0 0.0036 Response duration (months) 7.1 10.4 0.0014 Hazard ratio Survival (months) 15.6 20.3 0.00004 0.66 Progression-free survival (months) 6.2 10.6 <0.00001 0.54 Hurwitz H, et al. N Engl J Med. 2004 Jun 3;350(23):2335-42.
Survival 1.0 Probability of survival 0.8 0.6 0.4 0.2 IFL + placebo IFL + bevacizumab Hazard ratio = 0.66, p=0.00003 Median survival 15.6 (IFL + placebo) vs 20.3 months (IFL + bevacizumab) 0 0 10 20 30 40 Survival (months)
Fluorouracil/LV ± Bevacizumab Phase III Studie Kabbinavar, JCO 2005, 3706
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)
Bevacizumab Bevacizumab in in der der 2. 2. Linie Linie 1.0 Probability 0.8 HR=0.64 0.6 A vs B: p<0.0001 B vs C: p<0.0001 0.4 0.2 0 0 2 4 6 8 10 12 14 Progression-free survival (months) A: FOLFOX4 + bevacizumab B: FOLFOX4 C: Bevacizumab Total 273 273 229 Fail 228 241 215 16 Cens 45 32 14 18 20 Median 7.2 4.8 2.7 Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2)
Bevacizumab in der Standardtherapie des Kolonkarzinoms Chemotherapie: 1. Linie Anti-VEGF 5-FU Irinotecan Chemotherapie: 2. Linie Anti-VEGF 5-FU Oxaliplatin
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
EGF-R Expression in soliden Tumoren Kolorektal Lunge (NSCLC) HNO Kolorektal NSCLC HNO Mammakarzinom Ovalialkarzinom Nierenzellkarzinom 72-86% 40-91% 90-100% 14-91% 35-70% 50-90%
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
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
Ansprechen cetuximab + irinotecan (n=218) 60 56 [49-62] ** Percentage 50 40 30 20 10 23 [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)
Nebenwirkungen
Hauttoxizität und Ueberleben Skin reaction none any grade 2 Acneiform rash none any grade 2 Combination Response (%) 6.3 25.8 33.6 16.7 24.7 30.9 Survival (months) 3.0 9.1 10.8 5.8 8.9 10.8 Monotherapy Survival rate (%) 0.0 12.9 20.0 7.4 11.9 17.4 Survival (month) 2.5 8.1 9.6 5.3 7.5 9.4
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
Neoadjuvante Therapie von Lebermetastasen Metastasen auf Leber beschränkt (30%) Leberresektion (10-20%) 30-40% geheilt inoperabel kaum Langzeitüberleben
Lebermetastasenchirurgie Survival (%) 100 80 60 40 91% 66% 52% 48% Resectable: 335 Initially non-resectable: 138 30% 20 p=0.01 33% 23% 0 1 2 3 4 5 6 7 8 9 10 Years Adam, et al. Ann Surg 2004;240:644 657
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)
Therapieoptionen 50 45 40 35 30 25 20 15 10 5 0 RR % median survival:mos BSC 5FU FU/LV Cape CIFU IFL FOLFOX FOLFIRI FOLFOX IFL+B
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