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PreOP XRT: Oral fluoropyrimidines in randomized trials n NSABP R 04 open 1600 Cape vs. FU infusional (+/- Oxaliplatin 2x2 factorial) German Group open.

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Presentation on theme: "PreOP XRT: Oral fluoropyrimidines in randomized trials n NSABP R 04 open 1600 Cape vs. FU infusional (+/- Oxaliplatin 2x2 factorial) German Group open."— Presentation transcript:

1 PreOP XRT: Oral fluoropyrimidines in randomized trials n NSABP R 04 open 1600 Cape vs. FU infusional (+/- Oxaliplatin 2x2 factorial) German Group open ca. 180 Cape vs. FU infusional (pre- and postOP) Spanish Group ECCO 2005 149 UFT/FA vs. FU/FA no difference in pCR, local failure, toxicity

2 No Bolus-FU anymore in Coloncancer 5FU inf / FA André et al., J Clin Oncol 2003 Capecitabin Twelves et al., NEJM 2005

3 Präoperative Radiochemotherapie des Rektumkarzinoms

4 Rödel, Arnold et al., Int J Radiation Oncology Biol Physics 2008 Phase I/II Trial: Preoperative Radiotherapy with CAPOX and Cetuximab No increase of toxicity, No increase of perioperative complication rate

5 Tumor regression grading (Dworak and Keilholz 1997) Cet-Capox-RTCapox-RT* (n=46) (n=103) Complete Regression 9% 19% Good Regression (50 - 99%) 38% 55% Moderate Regression (25 - 50%) Poor Regression (< 25) 53% 26% No Regression *Rödel, Liersch, Arnold et al., J Clin Oncol 2007 Rödel, Arnold et al., Int J Radiation Oncology Biol Physics 2007

6 Phase II trials with intensified preoperative Radiochemotherapy N pts.pCR (%) 1 FU / Cape9 – 21 2 FU / CapeOxali16 – 33 FU / CapeIrino18 – 32 3 1 CapeCetuximab40 5 2 CapeOxaliCetuximab49 9 3 CapeIrinoCetuximab20 25 4 CapeIrinoCetuximab1020 Arnold et al., Eur J Cancer 2005 (Suppl.); 1Machiels, Ann Oncol 2007; 2Arnold, ASCO 2007, 3Hofheinz et al., Int J Radiat Oncol Biol Phys 2006; 4Bertolini ASCO 2007

7 Bevacizumab RT in rectal cancer Nchemotherapy Willett et al., ASCO 2007 225FU CI50.4 GyNo increase in toxicity pCR: 22% Czito et al., ASCO 2007 11XELOX50.4 GyLowered dose of Capecitabine due to diarrhea Privitera et al., ASCO 2007 11XELOX (6) XELIRI (5) 45.0 Gy.3 pts.: hypertension, no further toxicity

8 Colon cancer stage III: Oxaliplatin combinations > FU/FA André T et al., NEJM, 2004; Wolmark N et al., ASCO 2005 MOSAIC NSABP C07

9 Overall survival data: Supporting Oxaliplatin Combinations De Gramont et al., ASCO 2007 Kolon-Ca. St. III 71% Rektum-Ca. St. II/III 38%

10 CHemotheRapyOr No chemotherapy In CLEarmargins after neoadjuvantchemoradiationin locally advanced rectal cancer (CHRONICLE). With 800 patients and p<0.05: Primary endpoint : 3-yr DFS-85% power to detect a 10% increase ie. 40% -50% Secondary endpoints: overall survival, toxicity RANDOMIZATION Patients with locally advanced rectal cancer Capecitabine + Oxaliplatin 6 courses Follow-up only Pre-operative chemoradiation min 45Gy and fluoropyrimidine based chemotherapy RO resection achieved

11 baseline assessment within 14 days prior to randomization INVESTI- GATIONAL ARM capecitabine oxaliplatin RTx RANDOMIZATION locally advanced rectal cancer clinical stage T3 or T4 or any node- positive disease ECOG PS <2 CONTROL ARM capecitabine RTx INVESTI- GATIONAL ARM capecitabine oxaliplatin 6 cycles CONTROL ARM capecitabine 6 cycles follow-up max.2 weeks days 1-384-6 weeks SURGERY (TME) SURGERY (TME) 6-8 weeks18 weeks5 years Treatment Arms in PETACC-6

12 Capecitabine Oxaliplatin RTx RANDOMIZATION Locally Advanced Rectal Cancer Stage II or III 5-FU Oxaliplatin RTx FOLFOX + Bevacizumab 12 cycles * FOLFOX 12 cycles * SURGERY (TME) 5-FU RTx Capecitabine RTx RANDOMIZATION NSABP R-04 * Patients with neoadjuvant oxaliplatin receive up to 9 courses followed by 5- FU/Leucovorin with (arm II) or without (arm I) bevacizumab for up to 3 courses. US-Intergroup trial E5204 NSABP US-Intergroup Trial - Rectal Cancer N = 2100 N = 1606 2 x 2 factorial

13 Rödel et al. JCO 2007 Phase II Trial: Pre- and Postoperative (Radio-) Chemotherapy with XELOX

14 Neadjuvant XELOX followed by Chemoradiation in MRI defined Poor-Risk Rectal Cancer S Oxaliplatin xeloda Poor Risk:≥ 5mm into perirectal fat or ≤ 1mm to mesorectal fascia T3 at or below levators T1-4N2 CR+PR: 88% CR+PR: 97% pCR: 24% Chau I. et al. J Clin Oncol 2006 n=77

15 Predictors for pCR with Neoadjuvant Treatment Response%No Response%p TS0,20 low3141886 high10322168 P530,71 negative2151185 positive11263174 VEGF0,31 negative7331467 positive5172483 p210,74 negative418882 positive8252475 Negri et al. Br J Cancer 2008

16 Preoperative Radiochemotherapy in Rectal Cancer: VEGF as Prognostic factor? Giralt et al. Oncology 2006

17 Molecular Prognostic Factors To select the right patient for the right treatmentintensity Save toxicity and money Increase survival for those who need it But still 40-50% of the patients still die!!!!!

18 Capecitabin / Oxaliplatin = 5FU/FS / Oxaliplatin NO16966; Cassidy et al., ASCO 2007 1.Line HR 1.04 NO16967; 2nd line Rothenberg et al., ASCO 2007 HR 1.03 AIO 1.Line Porschen et al., JCO 2007 HR 1.17 TTD 1.Line Diaz Rubio et al., JCO 2007 HR 1.18 France 1.Line Ducreux et al., ASCO 2007 HR 1.00

19 Arkenau,..Schmoll,et al., ASCO GI 2008 Kombinationen mit Oxaliplatin: Metaanalyse der 1st line Studien PFS HR 1.05 (95%CI: 0.97- 1.14) OS HR 1.05 (95%CI: 0.92- 1.19) Capecitabin / Oxaliplatin = 5FU/FS / Oxaliplatin

20 Potentielle Molekulare Targets - Kolon-Ca. Growth factors, Rezeptoren, HER family, EGFR, IGF I/II Rec.… Angiogenese und Extracelluläre Matrix VEGF(R), MMPs, Integrine,.. Mechanismus für Cell Survival und Regulation der Apoptose Cyclin abh. Kinasen, mTOR, cGMP, COX2, p53, bcl-2 … Proteasom Tumor-assozierte Antigene Gangliosides, CEA, MAGE, EpCam Intracelluläres Signaling Ras, raf, MAPK, MEK, ERK, PKC, PI3K –IGF I/II

21 Saltz et al., ASCO 2007 RR-Rate gleich FOLFOX-beva 9.4 mos PFS 1 Monat besser XELOX-beva 9.3 mos. FOLFOX / XELOX +/- Bevacizumab N=1400 Gesamtüberleben gleich

22 CRYSTAL-Studie Van Cutsem et al., ASCO 2007

23 FOLFOX-4 + Cetuximab FOLFOX-4 EGFR- exprimierende mCRC Patienten Strata: ECOG 0-1,2 n=169 n=168 OPUS-Studie Bokemeyer et al., ASCO 2007

24 Cetuximab Kombinationen N Rem.-Rate Steigerung mit Cetuximab p CALGB FOLFOX or FOLFIRI 238+ 14%0.03 OPUSFOLFOX 337+ 10%0.06 CRYSTALFOLFIRI1200+ 8%0.004 Vennok et al., ASCO 2006; Bokemeyer et al., ASCO 2007; Van Cutsem et al., ASCO 2007

25 CRYSTAL - Studie: PFS Van Cutsem et al., ASCO 2007


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