PreOP XRT: Oral fluoropyrimidines in randomized trials

n

NSABP R 04 open

1600Cape vs. FU infusional (+/- Oxaliplatin 2x2 factorial)

German Group open

ca. 180Cape vs. FU infusional (pre- and postOP)

Spanish Group ECCO 2005

149UFT/FA vs. FU/FAno difference in pCR, local failure, toxicity

No Bolus-FU anymore in Coloncancer

5FU inf / FAAndré et al., J Clin Oncol

2003

CapecitabinTwelves et al., NEJM 2005

Präoperative Radiochemotherapie des Rektumkarzinoms

Rödel, Arnold et al., Int J Radiation Oncology Biol Physics 2008

Phase I/II Trial: Preoperative Radiotherapywith CAPOX and Cetuximab

No increase of toxicity,

No increase of

perioperative complication rate

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

2FU / Cape Oxali 16 – 33

FU / Cape Irino 18 – 32

3

1Cape Cetuximab 40 5

2Cape Oxali Cetuximab 49 9

3Cape Irino Cetuximab 20 25

4Cape Irino Cetuximab 10 20

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

N chemotherapy

Willett et al., ASCO 2007

22 5FU CI 50.4 Gy No increase in toxicitypCR: 22%

Czito et al., ASCO 2007

11 XELOX 50.4 Gy Lowered dose of Capecitabine due to diarrhea

Privitera et al., ASCO 2007

11 XELOX (6) XELIRI (5)

45.0 Gy. 3 pts.: hypertension, no further toxicity

Colon cancer stage III:Oxaliplatin combinations > FU/FA

André T et al., NEJM, 2004; Wolmark N et al., ASCO 2005

MOSAIC NSABP C07

Overall survival data: Supporting Oxaliplatin Combinations

De Gramont et al., ASCO 2007

Kolon-Ca. St. III 71%

Rektum-Ca. St. II/III 38%

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

RA

ND

OM

IZA

TIO

N

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

baseline assessment

within 14 days prior to

randomization

INVESTI-GATIONAL

ARM

capecitabine

oxaliplatin

RTx

RA

ND

OM

IZA

TIO

N

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

follow-up

max.2 weeks days 1-38 4-6 weeks

SU

RG

ER

Y(T

ME)

SU

RG

ER

Y(T

ME)

6-8 weeks 18 weeks 5 years

Treatment Arms in PETACC-6

CapecitabineOxaliplatin

RTx

RA

ND

OM

IZA

TIO

N

Locally Advanced

Rectal Cancer

Stage II

or III

5-FUOxaliplatin

RTx

FOLFOX + Bevacizumab12 cycles *

FOLFOX12 cycles *

SU

RG

ER

Y(T

ME)

5-FURTx

CapecitabineRTx

RA

ND

OM

IZA

TIO

N

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 = 2100N = 1606

2 x 2 factorial

Rödel et al. JCO 2007

Phase II Trial: Pre- and Postoperative (Radio-) Chemotherapy with XELOX

Neadjuvant XELOX followed by Chemoradiationin MRI defined Poor-Risk Rectal Cancer

SOxaliplatin

xeloda

Poor Risk: ≥ 5mm into perirectal fat or ≤ 1mm to mesorectal fasciaT3 at or below levatorsT1-4N2

CR+PR:88%

CR+PR:97%

pCR:24%

Chau I. et al. J Clin Oncol 2006

n=77

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 11 26 31 74

VEGF 0,31

negative 7 33 14 67

positive 5 17 24 83

p21 0,74

negative 4 18 8 82

positive 8 25 24 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

NO16966; Cassidy et al., ASCO 2007 1.Line

HR 1.04

NO16967; 2nd lineRothenberg 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

Arkenau, ..Schmoll,et al., ASCO GI 2008

Kombinationen mit Oxaliplatin: Metaanalyse der 1st line Studien

PFSHR 1.05

(95%CI: 0.97-1.14)

OSHR 1.05

(95%CI: 0.92-1.19)

Capecitabin / Oxaliplatin = 5FU/FS / Oxaliplatin

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 AntigeneGangliosides, CEA, MAGE,

EpCam

Intracelluläres Signaling

Ras, raf, MAPK, MEK, ERK, PKC, PI3K –IGF I/II

Saltz et al., ASCO 2007

RR-Rate gleich FOLFOX-beva 9.4 mos PFS 1 Monat besser XELOX-beva 9.3 mos.

FOLFOX / XELOX +/- BevacizumabN=1400

Gesamtüberleben gleich

CRYSTAL-Studie

Van Cutsem et al., ASCO 2007

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

Cetuximab Kombinationen

N Rem.-Rate

Steigerung mit Cetuximab

p

CALGBFOLFOX 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