rectal cancer: french prodige study: best of asco, beirut, july 2009 prof eric van cutsem, md, phd...
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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
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)