Neoadjuvant therapy of rectal cancer – how can we make it better? Claus Rödel

Neoadjuvant therapy of rectal cancer – how can

we make it better?

Claus RödelDepartment of Radiotherapy

University of Frankfurt, Germany

Honoraria: • Roche, • Sanofi-Aventis

Research Funding: • Merck• Roche

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?

OUTLINE

R5-FU: 350 mg/m²/d LV: 20 mg/m²/d

RT: 45 Gy

OP

5-FU: 350 mg/m²/d LV: 20 mg/m²/d

RT: 45 Gy

OP

5-FU: 350 mg/m²/d LV: 20 mg/m²/d

FFCD 9203

Gérard JP et al, J Clin Oncol 2006

FFCD 9203 – Local Failure

Gérard JP et al, J Clin Oncol 2006

RCT: 8.1%

RT: 16.5%

p < 0.05

Similar Results: EORTC 22921: Bosset et al., N Engl J Med 2006

Bujko et al., Br J Surg 2006

p=0.8p=0.17

9.0%

14.2%

T3NxM0 5 x 5 Gy 5-FU CRT P

Number of pts. 163 163

3-year LR rates 7.5% 4.4% 0.24

5-year M1 28% 31% 0.85

5-year OS 74% 70% 0.56

POLISH

AUSTRALIA

5 x 5 Gy versus 5-FU CRT ?

ASCO 2010: Ngan et al, abstract # 3509

50.4 GyRadiotherapy:

28 x 1.8 Gy

Chemotherapy:

Oxaliplatin50 mg/m²/d

Weeks 1 2 3 4 5 6

d 1 - 14 d 22 - 35Capecitabine1650 mg/m²/d

d1 d 8 d 22 d 29

Rödel et al., J Clin Oncol 2003 and J Clin Oncol 2007

Phase I/II Studies of RT with new agents

CAPOX-RT 5-FU-RT (n=110) (n=385)

Complete Regression (100%) 16% 10%Good Regression (> 50%) 59% 52%Moderate Regression (25-50%) 11% 14%Poor Regression (< 25) 10% 15%No Regression (0%) 3% 8%

Tumor-Regression-Grading

ACCORD 12/0405-Prodige 2

Gérard JP et al, J Clin Oncol 2010;28-1638-44

R

OPCape: 800 mg/m²/bid

45 Gy/1.8 Gy SD

AdjuvantChemotherapy (local policy)

OP

Oxaliplatin: 50 mg/m²/weekCape: 800 mg/m²/bid

50 Gy/2.0 Gy SD

AdjuvantChemotherapy (local policy)

ACCORD 12Preop. Cap 45

PreopCapox 50

P

Number of pts. 299 299

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)

CAO/ARO/AIO-04

RT 50.4 Gy + 5-FU(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+/-OXNSABP R-04: CAP-RT+/-OX vs. 5-FU-RT+/-OX

100%

100%

95%

96%

62% 57

%

57%

53%

52%

62%

70%

65%

Cap

Ox

TME

Compliance to (neo-) adjuvant CAPOX

cycle 1 cycle 2

cycle 3

cycle 5cycle 4

cycle 6

RT 50.4Gy

Rödel C. et al. J Clin Oncol 2007;25:110-117

Grupo Cáncer de Recto 3 Study

RRT 50.4 Gy +

Cape/OxaliplatinCAPOX 4#, q21 T

ME

Fernández-Martos C, J Clin Oncol, 2010;28:859-65

MRT- defined Poor Risk: ≤ 2mm to mesorectal fascia, low-lying T3, T3N+, T4

RT 50.4 Gy + Cape/Oxaliplatin

CAPOX 4#, q21

TME

CRT+TME+adjuvant CAPOX

N=52

Induction-CAPOX +

CRT + TMEN=56

P

R0 resection rates 87% 86% n.s.

pCR 13% 14% n.s.

Compliance4 X CAPOX 54% 91% <0.001

Toxicity (Grad 3/4) CAPOX-RT CAPOX

29%54%

23%19%

0.360.004

Fernández-Martos C, J Clin Oncol, 2010;28:859-65

ASCO 2010: Similar trial: Maréchal et al, abstract # 3637

50.4 Gy Radiotherapy:

28 x 1.8 Gy

Chemotherapy

Oxaliplatin(35-50 mg/m²/d)

d 1 - 14 d 22 - 35

Capecitabine(1650 mg/m²/d)

d 1 d 8 d 22 d 29

Week 2 6 1 3 4 5

d 1 d 8 d 22 d 29d 15 d 35d -7Cetuximab

1 x 400 mg/m²

6 x 250 mg/m²/d

-1

Rödel C et al., Int J Radiat Oncol Biol Phys 2008

Phase I/II Preoperative Radiotherapywith CAPOX and Cetuximab for Rectal Cancer

CAPOX-RT+CET (n=45)

Complete Regression (100%) 9% Good Regression (> 50%) 38%Moderate Regression (25-50%) 27%Minimal Regression (< 25) 22%No Regression (0%) 4%

CAPOX-RT(n=110)

16%59%11%10%3%

Tumor-Regression-Grading

Confirmed by a randomized phase II trial: McCollum et al., abstract #3635

Phase I/II Präop. Bevacizumab/5-FU/RT

Willett CG et al., Nat Med 2004Willett CG et al., J Clin Oncol 2009

50.4 Gy

5-FU-Inf

Day 1 8 15 29 43 52

BEV5-10 mg/kg

Before treatment

12d post Bevacizumab

Willett CG et al., Nat Med 2004

Phase I/II Preop. Bevacizumab/5-FU/RT

Willett CG et al., J Clin Oncol 2009

• 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%

MSKCC-Pilot trial without RTStage II/III, excluding T4 + low tumors needing APR

Schrag D et al., ASCO 2010, abstract 3511

OP

4 x Bev-FOLFOX 2 x FOLFOX(5-FU Chemo-RT only if SD/PD)

Results: 8/29 (27%) with pCR (all no CRT)

ASCO 2010: Ongoing trial: Fernandes-Martos et al., abstract #TPS169

ACOSOG Z6041: Local Excision uT2uN0 rectal cancer

Garcia-Aguilar, J. et al., ASCO 2010, abstract #3510

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

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?

OUTLINE

Biomarkers for Response to Chemoradiation

Ghadimi et al., J Clin Oncol 2005n=30, 50.4 Gy/5-FU54 differentially expressed genes for theendpoint TRG/Downstaging

Rimkus et al., Clin Gastroenterol Hepat 2008N=42, 45 Gy/5-FU43 differentially expressed genes for theendpoint TRG

No concordance with even one gene between the 2 studies!!

• …postoperative chemoradio-therapy: rectal cancer < 12 cm

from anal verge pT3-4 or pN+

• …preoperative RT (5x5 Gy): any rectal cancer < 15 cm

Clinicopathological Selection Easy in former times:

Pooled Analysis :Five US postoperative phase III studies, n=3791

Gunderson et al., J Clin Oncol 2004

• 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

„May not require RT“

Not included

Circumferential Resection Margin

MERCURY Study GroupBMJ 2006 Radiology 2007

Nagtegaal ID, Quirke P. , J Clin Oncol 2008

TN- and CRM-defined Risk Stratification

Burton et al. Br J Cancer 2006

Multidisciplinary team discussionn=197 rectal cancer patients

Surgery only:T1/2, T3a, N0/1, CRM-

116 (59%)

HistologicalCRM –

97%

Preop. CT+CRT:>T3a, N2, CRM-;CRM +, low T3

81 (41%)

HistologicalCRM -100% 75% Does pCRM- imply that these patients

do not benefit from preop. RT?

Preoperative Radiotherapy vs. Risk-adapted postoperative CRT: MRC CR07

5x5Gy+TME TME alone

5y-Local recurrence:

CRM + 13.8% 20.7% HR 0.64 (0.25-1.64)

CRM - 3.3% 8.9% HR 0.36 (0.23-0.57)

Sebag-Montefiore D et al., Lancet 2009:373:811-20

(Postop CRT only if CRM+)

• 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-)?

SUMMARY