1. Neoadjuvant therapy of rectal cancer – how can we make it better?
Claus Rödel
Department of Radiotherapy
University of Frankfurt, Germany
Honoraria:
Roche,
Sanofi-Aventis
Research Funding:
Merck
Roche

2. O U T L I N E
How can we make it more efficient (or less toxic)?
- RT with 5-FU - RT with 5-FU/Cape plus oxaliplatin - RT with targeted agents - induction chemotherapy - without RT?, radical surgery?
How can we select better? - molecular? - clinical?

3. FFCD 9203 R OP RT: 45 Gy Gérard JP et al, J Clin Oncol 2006
5-FU: 350 mg/m²/d LV: 20 mg/m²/d
RT: 45 Gy OP
Gérard JP et al, J Clin Oncol 2006

4. FFCD 9203 – Local Failure RT: 16.5% RCT: 8.1% p < 0.05
Gérard JP et al, J Clin Oncol 2006
Similar Results: EORTC 22921: Bosset et al., N Engl J Med 2006

5. ASCO 2010: Ngan et al, abstract # 3509
5 x 5 Gy versus 5-FU CRT ?
p=0.8
p=0.17
9.0%
14.2% P O L I S H
Bujko et al., Br J Surg 2006
AUSTRAL I A
T3NxM0
5 x 5 Gy
5-FU CRT P
Number of pts.
163
3-year LR rates
7.5%
4.4%
0.24
5-year M1
28%
31%
0.85
5-year OS
74%
70%
0.56
ASCO 2010: Ngan et al, abstract # 3509

6. Phase I/II Studies of RT with new agents
50.4 Gy
Radiotherapy:
28 x 1.8
Chemotherapy:
Oxaliplatin
50 mg/m²/d
Weeks 5 6 d d
Capecitabine
1650 mg/m²/d d1
d 8
d 22
d 29
Rödel et al., J Clin Oncol 2003 and J Clin Oncol 2007

7. Tumor-Regression-Grading
CAPOX-RT FU-RT
(n=110) (n=385)
Complete Regression (100%) % 10%
Good Regression (> 50%) % 52%
Moderate Regression (25-50%) 11% 14%
Poor Regression (< 25) % 15%
No Regression (0%) 3% 8%

8. ACCORD 12/0405-Prodige 2 R OP OP Cape: 800 mg/m²/bid Adjuvant
Chemotherapy (local policy) R
45 Gy/1.8 Gy SD OP
Oxaliplatin: 50 mg/m²/week
Cape: 800 mg/m²/bid
50 Gy/2.0 Gy SD
Adjuvant
Chemotherapy (local policy)
Gérard JP et al, J Clin Oncol 2010;

9. ypCR (primary endpoint) 13.9% 19.2% 0.09
ACCORD 12
Preop. Cap 45
Preop
Capox 50 P
Number of pts.
299
ypCR (primary endpoint)
13.9%
19.2%
0.09
ypCR+”few residual cells”
28.9%
39.4%
0.008
CRM: 0-2 mm
19.3%
9.9%
0.02
Acute Tox ≥ 3
11%
25%
<0.001
Similar results: STAR-Trial, Aschele C et al, J Clin Oncol 2009 (abstr. CRA4008)

10. CAO/ARO/AIO-04 R 5-FU RT 50.4 Gy + 5-FU 4#, q29 RT 50.4 Gy + mFOLFOX
(best arm CAO/ARO/AIO-94)
RT 50.4 Gy +
5-FU/Oxaliplatin T M E
5-FU
4#, q29
mFOLFOX
8#, q15 R
Similar Design: PETACC 6: CAP+/-OX-RT – TME – CAP+/-OX
NSABP R-04: CAP-RT+/-OX vs. 5-FU-RT+/-OX

11. Compliance to (neo-) adjuvant CAPOX
cycle 1
cycle 2
100 %
100 %
95 %
96 %
cycle 3
cycle 4
T M E
cycle 5
cycle 6
70 %
C a p
O x
65 %
62 %
62 %
57 %
57%
53 %
52 %
RT 50.4Gy
Rödel C. et al. J Clin Oncol 2007;25:

12. Grupo Cáncer de Recto 3 Study R
MRT- defined Poor Risk: ≤ 2mm to mesorectal fascia, low-lying T3, T3N+, T4
RT 50.4 Gy +
Cape/Oxaliplatin
CAPOX
4#, q21 T M E R
RT 50.4 Gy +
Cape/Oxaliplatin
CAPOX
4#, q21 T M E
Fernández-Martos C, J Clin Oncol, 2010;28:859-65

13. CRT+TME+ adjuvant CAPOX
Induction-CAPOX + CRT + TME
N=56 P
R0 resection rates
87%
86%
n.s.
pCR
13%
14%
Compliance 4 X CAPOX
54%
91%
<0.001
Toxicity (Grad 3/4)
CAPOX-RT
CAPOX
29%
23%
19%
0.36
0.004
Fernández-Martos C, J Clin Oncol, 2010;28:859-65
ASCO 2010: Similar trial: Maréchal et al, abstract # 3637

14. Rödel C et al., Int J Radiat Oncol Biol Phys 2008
Phase I/II Preoperative Radiotherapy with CAPOX and Cetuximab for Rectal Cancer
Radiotherapy:
50.4 Gy
28 x 1.8 Gy
Chemotherapy d d
Capecitabine
(1650 mg/m²/d)
Oxaliplatin
(35-50 mg/m²/d)
d 1
d 8
d 22
d 29
6 x 250 mg/m²/d
Cetuximab
d -7
d 1
d 8
d 15
d 22
d 29
d 35
1 x 400 mg/m²
Week -1 1 2 3 4 5 6
Rödel C et al., Int J Radiat Oncol Biol Phys 2008

15. Tumor-Regression-Grading
CAPOX-RT+CET
(n=45)
Complete Regression (100%) %
Good Regression (> 50%) %
Moderate Regression (25-50%) %
Minimal Regression (< 25) %
No Regression (0%) %
CAPOX-RT
(n=110)
16%
59%
11%
10% 3%
Confirmed by a randomized phase II trial: McCollum et al., abstract #3635

16. Phase I/II Präop. Bevacizumab/5-FU/RT
Day
50.4 Gy
5-FU-Inf
BEV
5-10
mg/kg
Willett CG et al., Nat Med 2004 Willett CG et al., J Clin Oncol 2009

17. Phase I/II Preop. Bevacizumab/5-FU/RT
Before treatment
12d post Bevacizumab
Willett CG et al., Nat Med 2004
ypT0: 5/32 (16%), ypN0:59%
No grad 4/5 tox; postop. complications: 13/32 (41%)
5-y local control: 100%
5y distant control: 75%
Willett CG et al., J Clin Oncol 2009

18. ASCO 2010: Ongoing trial: Fernandes-Martos et al., abstract #TPS169
MSKCC-Pilot trial without RT Stage II/III, excluding T4 + low tumors needing APR
4 x Bev-FOLFOX 2 x FOLFOX (5-FU Chemo-RT only if SD/PD) OP
Results: 8/29 (27%) with pCR (all no CRT)
Schrag D et al., ASCO 2010, abstract 3511
ASCO 2010: Ongoing trial: Fernandes-Martos et al., abstract #TPS169

19. Garcia-Aguilar, J. et al., ASCO 2010, abstract #3510
ACOSOG Z6041: Local Excision uT2uN0 rectal cancer
Oxaliplatin: 50 mg/m²/weeks 1,2,4,5
Cape: 725 mg/m² 5 days/week
50.4 Gy/1.8 Gy SD
Results: RO 98%; pCR 36/81 (44%), 6% ypT3
Garcia-Aguilar, J. et al., ASCO 2010, abstract #3510

20. O U T L I N E
How can we make it more efficient (or less toxic)?
- RT with 5-FU - RT with 5-FU/Cape plus oxaliplatin - RT with targeted agents - induction chemotherapy - without RT?, radical surgery?
How can we select better? - molecular? - clinical?

21. Biomarkers for Response to Chemoradiation
Ghadimi et al., J Clin Oncol 2005 n=30, 50.4 Gy/5-FU 54 differentially expressed genes for the
endpoint TRG/Downstaging
Rimkus et al., Clin Gastroenterol Hepat 2008
N=42, 45 Gy/5-FU
43 differentially expressed genes for the
endpoint TRG
No concordance with
even one gene between
the 2 studies!!

22. Clinicopathological Selection
Easy in former times:
…postoperative chemoradio-
therapy: rectal cancer < 12 cm from anal verge pT3-4 or pN+
…preoperative RT (5x5 Gy):
any rectal cancer < 15 cm

23. Five US postoperative phase III studies, n=3791
Pooled Analysis :
Five US postoperative phase III studies, n=3791
Low Risk
pT1-2/N0
Intermediate Risk
pT3/N0 and pT1-2/N1
Moderately high Risk
pT1-2/N2 and pT3/N1 and pT4/N0
High Risk
pT3/N2 and pT4/N1-2
Not included
„May not require RT“
Gunderson et al., J Clin Oncol 2004

24. Circumferential Resection Margin
MERCURY Study Group BMJ Radiology 2007
Nagtegaal ID, Quirke P. , J Clin Oncol 2008

25. TN- and CRM-defined Risk Stratification
Multidisciplinary team discussion n=197 rectal cancer patients
Surgery only:
T1/2, T3a, N0/1, CRM- 116 (59%)
Preop. CT+CRT:
>T3a, N2, CRM-;
CRM +, low T3 81 (41%)
Histological
CRM –
97%
Histological
CRM -
100%
75%
Does pCRM- imply that these patients do not benefit from preop. RT?
Burton et al. Br J Cancer 2006

26. Preoperative Radiotherapy vs. Risk-adapted postoperative CRT: MRC CR07
5x5Gy+TME TME alone
(Postop CRT only if CRM+)
5y-Local recurrence:
CRM % 20.7%
HR 0.64 ( )
CRM % 8.9%
HR 0.36 ( )
Sebag-Montefiore D et al., Lancet 2009:373:811-20

27. S
U M M A R Y
Neoadjuvant CRT with 5-FU - Inclusion of oxaliplatin CRT: ACCORD, STAR not convincing
NSAPB R-04 completed CRT+adj. CT: CAO/ARO/AIO-04 completed PETACC 6 open Ind.-CT+CRT: Grupo Cáncer de Recto 3 Study
- Inclusion of targeted agents: phase I/II without RT: subgroups (not T4, low) with local excision: subgroups (uT2N0)
Selection - molecular: investigational
- clinical: MRI-defined (CRM-)?