1. 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

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. 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

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

6. 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, Hofheinz et al., Int J Radiat Oncol Biol Phys 2006; 4Bertolini ASCO 2007

7. 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

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

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

10. 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

11. 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

12. 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

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

14. 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

15. 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

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
AIO 1.Line
Porschen et al.,
JCO 2007
HR 1.17
NO16966; Cassidy et al., ASCO 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

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

20. 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

21. 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

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

23. 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

24. 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

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