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

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

Präoperative Radiochemotherapie des Rektumkarzinoms

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

Tumor regression grading (Dworak and Keilholz 1997) Cet-Capox-RT Capox-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

Phase II trials with intensified preoperative Radiochemotherapy N pts. pCR (%) 1 FU / Cape 9 – 21 2 Oxali 16 – 33 Irino 18 – 32 3 1Cape Cetuximab 40 5 2Cape 49 9 3Cape 20 25 4Cape 10 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

Bevacizumab RT in rectal cancer chemotherapy Willett et al., ASCO 2007 22 5FU CI 50.4 Gy No increase in toxicity pCR: 22% Czito et al., ASCO 2007 11 XELOX Lowered dose of Capecitabine due to diarrhea Privitera et al., ASCO 2007 XELOX (6) XELIRI (5) 45.0 Gy. 3 pts.: hypertension, no further toxicity

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

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

CHemotheRapyOr No chemotherapy In CLEarmargins after neoadjuvantchemoradiationin locally advanced rectal cancer (CHRONICLE). RANDOMIZATION Follow-up only Patients with locally advanced rectal cancer Pre-operative chemoradiation min 45Gy and fluoropyrimidine based chemotherapy RO resection achieved Capecitabine + Oxaliplatin 6 courses 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

Treatment Arms in PETACC-6 locally advanced rectal cancer clinical stage T3 or T4 or any node-positive disease ECOG PS <2 CONTROL ARM capecitabine RTx SURGERY (TME) CONTROL ARM capecitabine 6 cycles RANDOMIZATION follow-up INVESTI-GATIONAL ARM capecitabine oxaliplatin RTx INVESTI-GATIONAL ARM capecitabine oxaliplatin 6 cycles SURGERY (TME) follow-up baseline assessment within 14 days prior to randomization max.2 weeks days 1-38 4-6 weeks 6-8 weeks 18 weeks 5 years

NSABP US-Intergroup Trial - Rectal Cancer 5-FU RTx FOLFOX 12 cycles * RANDOMIZATION RANDOMIZATION Locally Advanced Rectal Cancer Stage II or III 5-FU Oxaliplatin RTx SURGERY (TME) Capecitabine RTx FOLFOX + Bevacizumab 12 cycles * Capecitabine Oxaliplatin RTx * 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. 2 x 2 factorial N = 1606 NSABP R-04 N = 2100 US-Intergroup trial E5204

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

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

Predictors for pCR with Neoadjuvant Treatment Response % No Response p TS 0,20 low 3 14 18 86 high 10 32 21 68 P53 0,71 negative 2 15 11 85 positive 26 31 74 VEGF 0,31 7 33 67 5 17 24 83 p21 0,74 4 8 82 25 75 Negri et al. Br J Cancer 2008

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

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!!!!!

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

Capecitabin / Oxaliplatin = 5FU/FS / Oxaliplatin 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) Arkenau, ..Schmoll,et al., ASCO GI 2008

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

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

CRYSTAL-Studie Van Cutsem et al., ASCO 2007

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

Cetuximab Kombinationen Rem.-Rate Steigerung mit Cetuximab p CALGB FOLFOX or FOLFIRI 238 + 14% 0.03 OPUS FOLFOX 337 + 10% 0.06 CRYSTAL FOLFIRI 1200 + 8% 0.004 Vennok et al., ASCO 2006; Bokemeyer et al., ASCO 2007; Van Cutsem et al., ASCO 2007

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