Rectal Cancer: French Prodige Study:

Best of ASCO, Beirut, July 2009

Prof Eric Van Cutsem, MD, PhD

Digestive Oncology

Leuven, Belgium

30/05/2009 2

Nice

Results of the Prodige 2-ACCORD 12/0405

Randomized trial comparing two neoadjuvant

chemo-radiotherapy (Cape 45 vs Capox 50)

in patients with T3-4 rectal cancer.

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

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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

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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 2005 JCO 2006;24:4260

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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

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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)

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Primary end point :Complete sterilization of operative specimen

ypCR 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

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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

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Hypothesis – sample size

ypCR : 11% 20%

N = 590

for statistical power 85% (2 sided = 0.05)

- 3 years enrollment

- Database locked march 2009

Stratification : center – T stage – T site

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ACCORD 12/0405-Prodige 2-Design of trial

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

R45 Gy/5 w + Cap

50 Gy/5 w + Capox6 weeks TME

Adjuvant chemo left each institution (constant)

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

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1 2 3 4 5• Radiotherapy

44 Gy

50 Gy/25F/5 weeks

• Capecitabine 800/m²x2/Day (1600mg/m²) except WE

• Oxaliplatin IV 50 mg/m²(2h)

Capox 50

●

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Pathology

ypT0 N0 – R0Quirke - Dworak

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November 2005 - July 2008

598 pts / 2,9 years

56 centers

Age : 63 yM/F : 2/1T3 : 87% T2 : 8%

T4 : 5%

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RT45-Cap N= 299

RT50-CapOx N= 299

Eligible n= 293 Eligible n= 291

Surgery n= 287 Surgery n= 287

Operative specimen n= 285

Operative specimenn= 278563

574

584

598 randomized patients

Adj. Chemotherapy42%

Adj. Chemotherapy30%

Flow-Chart

598

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Early toxicity G2-3-4 (CTC –NCI V3)Adverse event Cape 45 (293) Capox 50 (291) p-value

All toxicity G3-4 11% (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)

Asco 2008 * < 44 Gy : 2%

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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)

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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

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Circumferential rectal margin - CRM

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 ??

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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

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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%

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STAR (747) ACCORD (598)

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

G3-4 toxicity 25%

ypCR 19% (increase)

Rectal Cancer T3-4 M0

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STAR (747) ACCORD (598)

RT 50.4 + Oxali (60 mg) RT50 + Capox

G3-4 toxicity 24% (increase) 25%

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

Rectal Cancer T3-4 M0

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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

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(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

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Oxaliplatin not a good radiosensitizer

Folkword – Radiat Oncol 2008;86:428

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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)

- Capecitabine 1600 mg/m² (RT days)

■ How to fight distant metastases ? (oxaliplatin)