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Rectal Cancer: French Prodige Study: Best of ASCO, Beirut, July 2009. Prof Eric Van Cutsem, MD, PhD Digestive Oncology Leuven, Belgium.

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Rectal Cancer:

French Prodige Study:

Best of ASCO,

Beirut, July 2009

Prof Eric Van Cutsem, MD, PhD

Digestive Oncology

Leuven, Belgium


Results of the Prodige 2-ACCORD 12/0405Randomized trial comparing two neoadjuvant chemo-radiotherapy (Cape 45 vs Capox 50)in patients with T3-4 rectal cancer.

Nice

Jean-Pierre GERARD, D. Azria, S. Gourgou-Bourgade, I. Martel-Laffay,

C. Hennequin, P.L. Etienne, V. Vendrely, T. Conroy, E. François, C. Montoto-Grillot,

for the FNCLCC - FFCD

No conflict of interest - Abstract # 31309 - ASCO – Orlando – 30 May 2009

30/05/2009


Background 1
Background (1)

■ Surgery "TME" (sharp dissection) cornerstone

of treatment of T3-4 M0 rectal cancer

■ German CAO/ARO Phase III trial (2004)

Preop CT-RT > postop (standard)

Local control - toxicity

30/05/2009


Background 2
Background (2)

Concurrent CT-RT > RT alone

FFCD 92.03 - (EORTC) phase III

RT CT - RT

ypCR 4% 11%

Loc rec 5 y 16% 7%

No change : sphincter preservation – survival

ASCO 2005JCO 2006;24:4260

30/05/2009


2005 how to optimize neoadjuvant treatment for t3 4 nx m0 rectal cancer
2005 : How to optimize neoadjuvant treatment for T3-4 Nx M0 rectal cancer ?

  • FFCD 92.03 : RT 45 Gy/5 weeks - 5 FU 225 mg/m²

  • ACCORD 12/0405-Prodige 2

    pragmatic approach : 2 modifications

  • RT dose increase : 50 Gy/5 weeks (BED + 15%)

  • CT intensification : Oxaliplatin (50 mg/m²)

    Capecitabine (1600 mg/m²/d) = 5FU - LV

30/05/2009


Accord 12 inclusion criteria
Accord 12 inclusion criteria rectal cancer ?

As in FFCD 92.03

■ Adenocarcinoma of rectum

■ Accessible to digital examination

■ T3-4 resectable N0-2 M0

T2 distal anterior rectum

- Workup = EUS – MRI – CT (Th. Abd)

30/05/2009


Primary end point complete sterilization of operative specimen ypcr dworak quirke
Primary end point : rectal cancer ?Complete sterilization of operative specimenypCR Dworak- Quirke

0 = no regression

1 = moderate pathological tumor response

2 = very few residual tumor cells

3 = no visible tumor cell (ypCR)

Dworak Int J Colorect Dis 1997;12:19 Quirke Lancet Oncol 2007;8:651

30/05/2009


Secondary end points
Secondary end points rectal cancer ?

■ circumferential rectal margin (CRM)

- 0 to< 1 mm (R0)

- 0 to< 2 mm

■ - Toxicity – sphincter preservation (AR)

- Local control – DFS - ov. Survival

- Bowel – sexual functions

30/05/2009


Hypothesis sample size
Hypothesis – sample size rectal cancer ?

ypCR : 11% 20%

N = 590

for statistical power 85% (2 sided a = 0.05)

- 3 years enrollment

- Database locked march 2009

Stratification : center – T stage – T site

30/05/2009


Accord 12 0405 prodige 2 design of trial

R rectal cancer ?

ACCORD 12/0405-Prodige 2-Design of trial

  • T3 (4) M0 - Accessible DRE < 80 y (low ant T2)

45 Gy/5 w + Cap

50 Gy/5 w + Capox

6 weeks TME

Adjuvant chemo left each institution (constant)

  • Hypothesis : ypCR = 11% 20% (590 pts)

30/05/2009


50 Gy/25F/5 weeks rectal cancer ?

Capox 50

44 Gy

• Radiotherapy

• Capecitabine

800/m²x2/Day

(1600mg/m²)

except WE

• Oxaliplatin IV

50 mg/m²(2h)

30/05/2009


Pathology rectal cancer ?

ypT0 N0 – R0

Quirke - Dworak

30/05/2009


November 2005 - July 2008 rectal cancer ?

598 pts / 2,9 years

56 centers

Age : 63 y

M/F : 2/1

T3 : 87% T2 : 8%

T4 : 5%

30/05/2009


Flow chart
Flow-Chart rectal cancer ?

598 randomized patients

RT45-Cap N= 299

RT50-CapOx N= 299

598

Eligible n= 293

Eligible n= 291

584

Surgery n= 287

Surgery n= 287

574

Operative specimen n= 285

Operative specimenn= 278

563

Adj. Chemotherapy42%

Adj. Chemotherapy30%

30/05/2009


Early toxicity g2 3 4 ctc nci v3
Early toxicity G2-3-4 (CTC –NCI V3) rectal cancer ?

Adverse event Cape 45 (293) Capox 50 (291) p-value

All toxicity G3-411%(32) 25%(74)<0.0001

Diarrhea G3-4 3% 13% < 0.0001

Haematol G3-4 4% 5%

Hand. foot G2 < 1% 0%

Periph. neurop. G2 0.4% 5% <0.002

RXT full dose 99% 90% *

Surgery 98%(287)99%(287)

* < 44 Gy : 2%

Asco 2008

30/05/2009


Surgical toxicity
Surgical toxicity rectal cancer ?

Event Cape 45 (287) Capox 50 (287) p-value

Ant. Resect. 73% (211) 76% (218) NS

Fistula (sgy) (AR) 3% (7) 2% (5)

2nd surg. 15% 16%

G2-3-4 med.compl. 21% (59) 18% (52)

Hospital stay (days) 15 15

Death 60 days 0.3% (1) 0.3% (1)

30/05/2009


Primary end point operative specimen sterilization ypcr dworak quirke
Primary end point – operative specimen rectal cancer ?Sterilization ypCR (Dworak-Quirke)

Cape 45 (282) Capox 50 (276) p-value

no visible cell (ypCR)14%(40)19%(53) 0.11

No + few residual cell 30% (85) 41% (113) 0.008

ypT0 14% 19% ns

yp N0 69% 71% ns

30/05/2009


Circumferential rectal margin crm
Circumferential rectal margin - CRM rectal cancer ?

Margin Cape 45 (162) Capox 50 (147) p-value

0-1 mm 12% (19) 7% (11)0 .21

0-2 mm 19% (31) 9% (14)0.017

Pelvic local control ??

30/05/2009


Weaknesses and limitations of study
Weaknesses and limitations of study rectal cancer ?

  • Short Follow up (12m) no clinical end point (loc. DFS)

  • Primary end point : not significant (ypCR) (0.11)

  • ypCR : not a good surrogate end point

  • Two modifications : RT dose – oxaliplatin

    BUT : good overview of French clinical practice

    56 institutions (30 academic) 2006-2008

30/05/2009


Summary main results capox 50
Summary Main results "Capox 50" rectal cancer ?

  • Early G3-4 toxicity : increased 25%

  • Surgery performed : no detriment 99%

  • Operative death (60 days) : low 0.3%

  • Sphincter preservation : no increase 75%

  • CRM "negative" trend ++ 93%

  • ypCR trend ++ 19%

30/05/2009


Rectal Cancer T3-4 M0 rectal cancer ?

STAR(747)ACCORD(598)

RT50.4 + Oxali (60 mg)RT50 + Capox

G3-4 toxicity 25%

ypCR 19% (increase)

30/05/2009


Rectal Cancer T3-4 M0 rectal cancer ?

STAR(747)ACCORD(598)

RT 50.4 +Oxali (60 mg)RT50 + Capox

G3-4 toxicity 24% (increase) 25%

ypCR 16% (no difference) 19% (increase)

30/05/2009


When analysing the results of rectal cancer ?ACCORD 12 trial

with reference to the STAR trial

the following comments and suggestions

can be made regarding :

(1) Oxaliplatin (2) Dose of RT (3) Capecitabine

30/05/2009


(1) Oxaliplatin rectal cancer ? increases toxicity (diarrhea) without

impact on ypCR (not radiosensitizer) (occult. M1 ?)

(2) 50 Gy/5 weeks compatible with surgery and

increase ypCR and CRM "negative" (RX dose effect)

(3) Capecitabine has the same activity as 5FU

30/05/2009


Oxaliplatin not a good radiosensitizer rectal cancer ?

Folkword – Radiat Oncol 2008;86:428

30/05/2009


Proposal cape 50 regimen
Proposal rectal cancer ?: "Cape 50" regimen

■ For T3-4 Nx M0 rectal cancers (resectable)

Good option for neoadjuvant treatment

- RT 50 Gy/5 weeks(2 Gy/fraction/25 F)

- Capecitabine1600 mg/m²(RT days)

■ How to fight distant metastases ? (oxaliplatin)

30/05/2009


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