Discussion abstracts 4006-4009

Alberto Sobrero MD

Ospedale San Martino

Genoa , Italy

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

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”

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

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

4006, Meyers : implications

• Trials - Stratification factor

• Practice - empyrical evidence of what has been common practice

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

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

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

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4

NSABP C-07 : DFS

FLOX

FU LV

YEARS

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

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

Biologics in the adjuvant setting : the Trastuzumab experience

early DFS early OS long term OS

Yes Yes ?

CAUTION: BIOLOGICS MAY IMPACT DFS DIFFERENTLY

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

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

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

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 !

• 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

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

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

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)

How much absolute reduction in recurrence makes adjuvant CT worth for patients ( N= 150)?

1/3 = 1%

2/3 = 5%

N. Love , ASCO 2007

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%

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

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

Relevance: conclusion

TRIALS PRACTICE

L. Node ratio + -

Folfox - +

early DFS ? +

Clin. Px factors ++ ++

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