discussion abstracts 4006-4009
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Discussion abstracts 4006-4009. Alberto Sobrero MD Ospedale San Martino Genoa , Italy. Abstracts 4006-4009. Meyers4006l.node ratioRectal De Gramont4007Mosaic Colon Sargent4008early DFSColon O’ Connell4009Px factorsColon. very predictable results - PowerPoint PPT PresentationTRANSCRIPT
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Discussion abstracts 4006-4009
Alberto Sobrero MD
Ospedale San Martino
Genoa , Italy
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Abstracts 4006-4009
Meyers 4006 l.node ratio Rectal
De Gramont 4007 Mosaic Colon
Sargent 4008 early DFS Colon
O’ Connell 4009 Px factors Colon
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THE LYMPH NODE WORLD OF THE SURGEON & PATHOLOGIST
Surgeon “ What do you mean there were only 4 l.-nodes in the rectal cancer
specimen?”
Pathologist “ That is all I could find “
Surgeon “Perhaps you ought to look harder “
Pathologist “Perhaps you ought to work harder at surgery”
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Ratio of Metastatic/ Examined Lymph Nodes:Predictor of Overall Survival in Rectal Cancer
• LN ratio was the strongest predictor of overall survival.
• Predicts survival whether N1, N2, small or
large number of LN’s examined
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RATIO OF METASTATIC /EXAMINED LYMPH NODES
Colon Cancer Berger , J Clin Oncol,2005
Gastric Cancer Inoue , Ann Surg Oncol, 2002
Pancreatic Cancer Slidell, SEER database
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4006, Meyers : implications
• Trials - Stratification factor
• Practice - empyrical evidence of what has been common practice
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4008, Sargent
1. Adjuvant FU CT prevents most relapses within 2 years
2. Benefit DFS benefit OS adjuvant FU CT:curative
3. Chances of recurring after 5 yrs < 5%
4. Standard approaches to trial design : OK
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4008, Sargent
1. Adjuvant FU CT prevents most relapses within 2 years
2. Benefit DFS benefit OS adjuvant FU CT:curative
3. Chances of recurring after 5 yrs < 5%
4. Standard approaches to trial design : OK
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Disease-free Survival: ITT
Data cut-off: June 2006
HR [95% CI]: 0.80 [0.68–0.93]
p=0.003
Months
FOLFOX4
LV5FU2
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54
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0.5
0.6
0.7
0.8
0.9
1
0 1 2 3 4
NSABP C-07 : DFS
FLOX
FU LV
YEARS
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Overall Survival: ITT
HR [95% CI]: 0.85 [0.72–1.01]
p=0.057
Data cut-off: January 2007
Months
FOLFOX4
LV5FU2
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90
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4008, Sargent
1. Adjuvant FU CT prevents most relapses within 2 years
2. Benefit DFS benefit OS adjuvant FU CT:curative
3. Chances of recurring after 5 yrs < 5%
4. Standard approaches to trial design : OK
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Biologics in the adjuvant setting : the Trastuzumab experience
early DFS early OS long term OS
Yes Yes ?
CAUTION: BIOLOGICS MAY IMPACT DFS DIFFERENTLY
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4008, Sargent
1. Benefit DFS within 2 years , not later
2. Benefit DFS benefit OS adjuvant CT:curative
3. Chances of recurring after 5 yrs < 5%
4. Standard exponential model is OK
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CM923700-15
Time to recurrence curve flattens after Time to recurrence curve flattens after 5 years5 years(Moertel et al,NEJM 1990)(Moertel et al,NEJM 1990)
Time to recurrence curve flattens after Time to recurrence curve flattens after 5 years5 years(Moertel et al,NEJM 1990)(Moertel et al,NEJM 1990)
FU levamisole
control
% p
ts f
ree
fro
m r
ec
urr
en
ce
Years from registration 1 2 3 4 5 6 7 8 9
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CM923700-16
DFS curve continues to decline DFS curve continues to decline (Haller et al,JCO 2005)(Haller et al,JCO 2005)
DFS curve continues to decline DFS curve continues to decline (Haller et al,JCO 2005)(Haller et al,JCO 2005)
INT 0089
FU based adjuvant regimens
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4008, Sargent: implications
• Trials– early DFS as endpoint in CT trials : OK– early DFS as endpoint in trials on bio: careful – RFS vs DFS (Punt et al. JNCI 2007)
• Practice– No relapse within 5 yrs “celebrate!” (1/20)– Long term F/U Yes, but different – If late relapses rare be sure of diagnosis !
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• Impact of “hystorical” clinical px factors on outcome HR, survival
– RFS > 3 yrs 0.6– Initial stage II 0.6– No adjuvant 0.8
• Impact of therapy on outcome – Beva + IFL 0.6– Beva + folfox 0.8 (PFS)– Cetuximab+ Irinot. 0.7 (PFS)
• Clinically relevant treatment effects may be about the same magnitude as potential biases !
4009, O’ Connell
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Time from Relapse to Death: ITT
Patients alive with relapse (%)
FOLFOX4 69 (6.1)
LV5FU2 88 (7.8)
Months
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
FOLFOX4
LV5FU2
0 6 12 18 24 6030 36 42 48 54 66 8472 78
Data cut-off: January 2007
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4009, O’ Connell : implications
1. Trials• Inadequacy of stage IV definition
• Room for improvement of px assessment on clinical ground– Combining historical and classical
• If px groups can be better identified:– Single arm phase II in poor px patients ….?– Window of op. trials with bio single agent in good px pts
2. Practice• general paradigm for non surgical stage IV
– lines of treatment vs continuum of care FOCUS, LIFE, CAIRO, GISCAD, OPTIMOX 2
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4007, De Gramont : Mosaic
1. Relevant Δ DFS
2. Consistent with NSABP C-07
3. OS benefitBUT
4. Substantial neuro toxicity (11.4% at 4 yrs)
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How much absolute reduction in recurrence makes adjuvant CT worth for patients ( N= 150)?
1/3 = 1%
2/3 = 5%
N. Love , ASCO 2007
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Mosaic: 5-YR DFS
Stage HR Δ
III .78 .005 7.5%
II high risk .74 ns 7.2%
II and III .80 .003 5.9%
II .84 ns 3.8%
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Future of adjuvant folfox
1. Combination with biologics • Bevacizumab ( Avant , NSABP C-08)• Cetuximab ( Petacc-8, NO146)
2. Reduce neurotoxicity• Reduce duration ( Italian 3 vs 6; SCOT)• Use of neuroprotectors ( Xaliproden)
3. Limit oxali to high risk patients
4. No oxali • Quasar 2
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UK QUASAR2: adjuvant Cape± Bevacizumab
Cape 8 cycles (24 weeks)
Cape8 cycles (24 weeks)
Bevacizumab 16 cycles (48 weeks)
Stage II / IIIcolon cancer
n=3 510
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Relevance: conclusion
TRIALS PRACTICE
L. Node ratio + -
Folfox - +
early DFS ? +
Clin. Px factors ++ ++
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Peripheral Sensory Neuropathy%
of
trea
ted
pat
ien
ts
48.1
30.9
22.2
1412
8.8
31.4
7.24.2 2.9 1.7 2.1
12.5
1.4 1.2 0.5 0.5 0.50
10
20
30
40
50
60
During Tx 6 months 1 year 2 years 3 years 4 years
Grade 1
Grade 2
Grade 3
27.6 17.4 14.2 11.4