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Adjuvant Therapy of Colon Cancer: Where are we now ?. Leonard Saltz, MD Memorial Sloan Kettering Cancer Center New York, NY. Why do we give adjuvant treatment?. Why do we give adjuvant treatment?. “Because its there.”. The Drug Development Paradigm. - PowerPoint PPT Presentation
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Adjuvant Therapy of Colon Cancer: Where are we now ?
Leonard Saltz, MD
Memorial Sloan Kettering Cancer Center
New York, NY
Why do we give adjuvant treatment?
Why do we give adjuvant treatment?
“Because its there.”
The Drug Development Paradigm• Identify a new active agent in refractory
disease.• Combine that active agent with standard
agent(s) in refractory disease.• Take new active combination to front line
phase III metastatic trial.• Move new front line metastatic therapy into
adjuvant trials to try to increase the cure rate.
• But…..
Maybe this paradigm is wrong.
00
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
00 33 66 99 1212 1515 1818 2121
MonthsMonths
Pro
bab
ilit
yP
roba
bil
ity
Survival: Second Line IrinotecanCunningham et al. Lancet 352:1413, 1998.
p=0.0001*p=0.0001*
CPT-11CPT-11
BSCBSC
*log-rank test*log-rank test
Phase III Irinotecan/5FU/LV in Metastatic Colorectal Cancer
(from Saltz et al,NEJM, 2000) 5FU/LV
Irinotecan 5FU/LV
Response rate 28 % 51 %
PFS 4.0 m 7.3 m
Grade 3-4 diarrhea 13 % 23%
Grade 4 neutropenia 43 % 24%
Grade 3 neuropathy 0% 0%
Median Survival 12.6 m 14.8 m (P=.04)
PFS = progression-free survival
Infusional 5FU/LV +/- Irinotecan Overall Survival (Douillard et al)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 6 12 18 24 30
Months
Pro
bab
ility
CPT-11/5-FU/LV (N=198)
5-FU/LV (N=187)
p=0.03*
Censored
* log-rank test* log-rank test
C89803: IFL vs. FL (Stage III)Failure-Free Survival by Arm
0 1 2 3 4
Years from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n F
ail
ure
-Fre
e
p=0.89
(All Patients)
5-FU/LVCPT-11/5-FU/LV
C89803: IFL vs. FL (Stage III)Overall Survival by Arm
0 1 2 3 4
Years from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n S
urv
ivin
g
(All Patients)
5-FU/LVCPT-11/5-FU/LV
p=0.81
Bolus vs Biweekly Infusional 5FU/LVin Metastatic CRC
De Gramont et al. JCO Feb 1 1997: 808-815
p=.067 62 wks 57 wksSurvival
p=.0004 11% 24%Gr3/4 tox
p=.0012 28 wks 22 wksPFS
p=.0004 33 % 14 %RR
Infusion N=217
Bolus N=216
FNCLCC ACCORD-02/FFCD 9802, ASCO 2005
0.0
00
.25
0.5
00
.75
1.0
0Pr
ob
ab
ility
0 1 2 3 4 5 6Years
LV5FU2 LV5FU2+IRITreatment
HR=1.19: 95%CI[0.90 - 1.59]
p=0.22
Disease-Free Survival
3-year DFS: 60% vs. 51%
FNCLCC ACCORD-02/FFCD 9802, ASCO 2005
0.0
00
.25
0.5
00
.75
1.0
0Pr
ob
ab
ility
0 1 2 3 4 5 6Years
LV5FU2 LV5FU2+IRITreatment
HR=1.06: 95%CI[0.79 - 1.42]
p=0.68
Disease-Free Survival adjusted for T Stage and N+
3-year DFS: 59% vs. 53%
Phase III Oxaliplatin/5FU/LV in Metastatic Colorectal Cancer
(from DeGramont. J Clin Oncol 18:2938, 2000)
5FU/LV 5FU/LV/Oxali
Response rate 22 % 51 %
PFS 6.2 m 9.0 m
Grade 3-4 diarrhea 5 % 12%
Grade 4 neutropenia 2 % 12%
Grade 3 neuropathy 0% 18.2%
Median Survival 14.7 m 16.2 m (P=.12)
PFS = progression-free survival
MOSAIC: Stage II + IIIDisease-free Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.3
0.4
0.2
0.1
0.0 0 666 12 18 24 30 36 42 48 54 60
Months
Events
FOLFOX4 279/1123 (24.8%)
LV5FU2 345/1123 (30.7%)
HR [95% CI]: 0.77 [0.65 – 0.90]
DF
S p
rob
abil
ity
Data cut-off: January 16, 2005
MOSAIC: Disease-free Survival Stage II and Stage III Patients
1.0
0.9
0.8
0.7
0.6
0.5
0.3
0.4
0.2
0.1
0.0 0
FOLFOX4 – Stage IILV5FU2 – Stage IIFOLFOX4 – Stage IIILV5FU2 – Stage IIIHR [95% CI]:
0.82 [0.60 – 1.13] Stage II0.75 [0.62 – 0.89] Stage III
Months
DF
S p
rob
abil
ity
666 12 18 24 30 36 42 48 54 60Data cut-off: January 16, 2005
Disease-free Survival in Stage III Patients: N1 & N2
1.0
0.9
0.8
0.7
0.6
0.5
0.3
0.4
0.2
0.1
0.0 0
FOLFOX4 – N1LV5FU2 – N1
FOLFOX4 – N2 LV5FU2 – N2
Months
DF
S p
rob
abil
ity
666 12 18 24 30 36 42 48 54 60Data cut-off: January 16, 2005
7.2%
11.5%
HR: 0.76
HR: 0.72
FU B RestLV 500
FU 500 Rest
LV 500
OHP 8585 2hr2hr
500
Week 1 2 3 4 5 6 7 8
R
NSABP C-07
2hr
x3
0.5
0.6
0.7
0.8
0.9
1
0 1 2 3 4
Ev # 3yr DFSFLOX 272 76.5%FULV 332 71.6%
p < 0.004HR: 0.79 [0.67 – 0.93]
21 % risk reduction
NSABP C-07 Trial (FLOX vs. FULV) 3 year Disease-Free Survival
Possible Conclusions
• Maybe our drug development paradigm is wrong?
• Corollary: How tumor cells survive therapy in the adjuvant (minimal disease) setting may differ from how they survive in the bulky metastatic setting.
• Therefore: what works in the metastatic setting may not work in the adjuvant setting and vice versa.
Does FLOX = FOLFOX ??
Oxaliplatin + Bolus vs. Infusion 5FU in Metastatic CRC: The TREE Studies
TREE-1 #pts RR*mFOLFOX6 41 47% bFOL 39 32% (p=.049)
TREE-2mFOLFOX6/bev 71 62%bFOL/bev 70 43% (p=.029)
*Responses unconfirmed
H Hochster: Presented at GI symposium Jan 05
Cross-Study ComparisonEfficacyFOLFOX 4
(MOSAIC)
FLOX
(C-07)
3 Year DFS 78 % 77 %
% improvement over 5FU/LV
5 % 5 %
Hazard Ratio 0.77 0.79
Cross-Study ComparisonToxicityFOLFOX 4
(MOSAIC)
FLOX
(C-07)
Gr 3-4 Neutropenia
41%
(2% neut. fever)
4%
Gr 3-4
Diarrhea
11% 38%
All Cause Mortality
0.5% 1%
Planned Oxaliplatin Usage
FOLFOX 4
(MOSAIC)
FLOX
(C-07)
# office visits for treatment
24
(12 for mFOLFOX 6)
18
# oxali doses 12 9
Oxali cost (ASP+6%)
1.8 m2
$39,552 $29,664
Do we need 12 doses of oxaliplatin when using FOLFOX?
9 ??
6 ??
Do we need 500 mg/m2 of LV?
QUASAR TRIAL
Is Disease Free Survival the true Endpoint?
FOLFOX4
LV5FU2
HR [95% CI]: 0.91 [0.75 – 1.11]
MOSAIC: Overall Survival1.0
0.9
0.8
0.7
0.6
0.5
0.3
0.4
0.2
0.1
0.0 0 666 12 18 24 30 36 42 48 54 60
Months
OS
pro
bab
ilit
y
Data cut-off: January 16, 2005
RANDOMI
Z ATION FOLFIRIFOLFIRI
FOLFOXFOLFOX
FOLFOX/ FOLFIRI
Phase III Stage III Adjuvant Intergroup N0147
Accrual ~ 250
RANDOMI
Z ATION FOLFIRIFOLFIRI
FOLFOXFOLFOX
FOLFOX/ FOLFIRI
Phase III Stage III Adjuvant N0147
+/-Cetuxima
b
RANDOMI
Z ATION
FOLFOX + Cetuximab
FOLFOX + Cetuximab
FOLFOXFOLFOX
Phase III Stage III Adjuvant (N0147)Possible Modification:
RANDOMI
Z ATION
FOLFOX + Bev
FOLFOX + Bev
FOLFOXFOLFOX
NSABP C-08
Phase III Trial, Stage II and IIIColon Cancer
RANDOMI
Z ATION
FOLFOX + Bev
FOLFOX + Bev
FOLFOXFOLFOX
NSABP C-08
Phase III Trial, Stage II and IIIColon Cancer
6 months bev
alone
→
Average Selling Price (ASP) + 6%(Patient assumption: 75 kg, 1.8 m2 patient, two weeks Rx)
• 5FU 500 mg/m2 $ 7• Leucovorin 500 mg/m2 $ 47• Xeloda 2000 mg/m2/d $ 1065• Camptosar 180 mg/m2 $ 2135• Eloxatin 85 mg/m2 $ 3296
• Avastin 5 mg/kg $ 2283• Erbitux 250 mg/m2 $ 4964
Adjuvant Therapy of Colon Cancer
Estimated Cost Per Patient (ASP + 6%)
5FU/LV (HD)
5FU/LV (LD)
FLOX
FOLFOX
FOLFOX/cetuximab
FOLFOX/bev 6 m
FOLFOX/bev 12 m
$954
$162
$30,618
$40,506
$100,074
$67,902
$95,298
Estimated Cost Per Year if 55,000 Patients Treated (ASP + 6%)
5FU/LV (HD)
5FU/LV (LD)
FLOX
FOLFOX
FOLFOX/cetuximab
FOLFOX/Bev 6 m
FOLFOX/Bev 12 m
$55,000,000
$9,000,000
$1,680,000,000
$2,230,000,000
$5,500,000,000
$3,730,000,000
$5,240,000,000
Challenges
• Evaluate duration of therapy questions
• Select therapies rationally– Molecular markers– Genetics
• Assure availability of appropriate therapies to all patients
Conclusions
• Until we do the trial, we don’t know the answer.
• Negative trials are as helpful and informative as positive trials.
Conclusions
• Adjuvant treatment options for colon cancer patients are better than they were, but not as good as they need to be.
• Please offer clinical trials to your patients. Without your help and theirs, we can’t make the progress that we so desperately need.