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Rectal Cancer: French Prodige Study: Best of ASCO, Beirut, July 2009 PowerPoint PPT Presentation


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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

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Rectal cancer french prodige study best of asco beirut july 2009

Rectal Cancer:

French Prodige Study:

Best of ASCO,

Beirut, July 2009

Prof Eric Van Cutsem, MD, PhD

Digestive Oncology

Leuven, Belgium


Rectal cancer french prodige study best of asco beirut july 2009

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

RTCT - RT

ypCR 4%11%

Loc rec 5 y16%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

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 :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

■ 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

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

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


Rectal cancer french prodige study best of asco beirut july 2009

50 Gy/25F/5 weeks

Capox 50

44 Gy

• Radiotherapy

• Capecitabine

800/m²x2/Day

(1600mg/m²)

except WE

• Oxaliplatin IV

50 mg/m²(2h)

30/05/2009


Rectal cancer french prodige study best of asco beirut july 2009

Pathology

ypT0 N0 – R0

Quirke - Dworak

30/05/2009


Rectal cancer french prodige study best of asco beirut july 2009

November 2005 - July 2008

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

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)

Adverse eventCape 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

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 specimenSterilization 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

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

0-1 mm12% (19)7% (11)0 .21

0-2 mm19% (31)9% (14)0.017

Pelvic local control ??

30/05/2009


Weaknesses and limitations of study

Weaknesses and limitations of study

  • 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"

  • 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 french prodige study best of asco beirut july 2009

Rectal Cancer T3-4 M0

STAR(747)ACCORD(598)

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

G3-4 toxicity 25%

ypCR 19% (increase)

30/05/2009


Rectal cancer french prodige study best of asco beirut july 2009

Rectal Cancer T3-4 M0

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


Rectal cancer french prodige study best of asco beirut july 2009

When analysing the results of 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


Rectal cancer french prodige study best of asco beirut july 2009

(1) Oxaliplatin 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


Rectal cancer french prodige study best of asco beirut july 2009

Oxaliplatin not a good radiosensitizer

Folkword – Radiat Oncol 2008;86:428

30/05/2009


Proposal cape 50 regimen

Proposal: "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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