Minimal versus Intense Upfront Systemic Therapy in Metastatic
Colorectal Cancer
Paulo M. Hoff, MD, FACPHospital Sirio Libanes
Sao Paulo, Brazil
Centro de Oncologia
Medical Oncology Treatment Objectives in CRC
• To cure patients:
– Adjuvant chemotherapy
– Convert inoperable into operable disease
• To palliate symptoms:
– Reduce tumor volume
• To prolong survival
– Control disease growth
5 – Fluorouracil: 1957
NH
HN
O
O
F
5-FU
50 years later, fluoropyrimidines remain the backbone of colorectal cancer treatment.
Treatment Options for Advanced Colorectal Cancer in 2006
• Six different classes of drugs available:– Fluoropyrimidines
• 5-FU, FUDR, Capecitabine, UFT, S-1
– Platins • Oxaliplatin
– Topoisomerase I inhibitors • Irinotecan
– Direct TS inhibitors• Raltitrexed
– Anti-VEGF • Bevacizumab
– Anti-EGFR • Cetuximab, Panitumumab
Irinotecan Combination Trials
IFL* IFL* (n=231)(n=231)
5-FU/LV(n=226)
RRAANNDDOOMMII
Z Z EE IrinotecanIrinotecan
(n=226)(n=226)
Saltz et al. Saltz et al. N Engl J MedN Engl J Med. 2000;343:905-914. 2000;343:905-914
Metastatic Colorectal
Cancer
Saltz et al. Saltz et al. N Engl J MedN Engl J Med. 2000;343:905-914.. 2000;343:905-914.
Irinotecan Combination Trials: Efficacy
Irinotecan + 5-FU/LV 5-FU/LV P Value
RR (confirmed, %) 39% 21% <.001*
PFS (median, mo) 7.0 4.3 .004
OS (median, mo) 14.8 12.6 .04
Oxaliplatin as Second-Line Treatment for CRC
Rothenberg et al. Rothenberg et al. J Clin OncolJ Clin Oncol. 2003;21:2059-2069.. 2003;21:2059-2069.
LV5FU2(n=151)
Oxaliplatin(n=156)
R
A
N
D
O
M
I
Z
E
FOLFOX4(n=152)
Metastatic Colorectal
Cancer S/P IFL
Oxaliplatin as Second-Line Treatment for CRC
LV5FU2 FOLFOX4 Oxaliplatin P Value
RR 0% 9.9% 1.3%
<.0001
TTP 2.7 mo 4.6 mo 1.6 mo <.0001
Overall Survival
8.7 mo 9.8 mo 8.1 mo .07
Rothenberg et al. Rothenberg et al. J Clin OncolJ Clin Oncol.. 2003;21:2059-2069. 2003;21:2059-2069.
N9741: Modified Schema
IFLIFL(n=264)(n=264)
IROX(n=264)
FOLFOX4FOLFOX4(n=267)(n=267)
Goldberg et al. Goldberg et al. J Clin OncolJ Clin Oncol. 2004;22:23-30.. 2004;22:23-30.
R
A
N
D
O
M
I
Z
E
Metastatic Colorectal
Cancer
N9741: Efficacy Results
IFL(N=264)
FOLFOX(N=267)
IROX(N=264)
RR (CR + PR) 31% 45% 34%
Median TTP (Months)
6.9 8.7 6.5
Median OS
(Months) 14.8 19.5 17
Goldberg et al. Goldberg et al. J Clin OncolJ Clin Oncol. 2004;22:23-30.. 2004;22:23-30.
N9741: Second Line Treatment
Saltz FOLFOX-4 WassermanCPT-11 Oxaliplatin CPT-11
5-FU/LV 5-FU/LV OxaliplatinN=235 N=235 N=237
Any 59% 67% 63%
CPT-11 22% 52% 28%
Oxaliplatin 17% 6% 6%
5-FU 35% 33% 45%
Other 28% 20% 27%
FOLFOX6(n=111)
FOLFIRI With FOLFOX6 Sequencing Trial in CRC
Tournigand et al. Tournigand et al. J Clin Oncol.J Clin Oncol. 2004;22:229-237. 2004;22:229-237.
FOLFIRI(n=109)
R
A
N
D
O
M
I
Z
E
FOLFIRI(n=69)
FOLFOX6(n=81)Until
progression
Untilprogression
Untilprogression
Untilprogression
RR, % 56 15 54 4
PFS, mo 8.5 4.2 8.0 2.5
OS, mo 21.5 20.6
FOLFIRI FOLFOX6 FOLFOX6 FOLFIRI n = 109 n = 81 n = 111 n = 69
Tournigand C et al. J Clin Oncol 2004;22:229-237
FOLFIRI With FOLFOX6 Sequencing Trial in CRC
Availability of All Cytotoxic Agents and Survival
Grothey A and Sargent D. J Clin Oncol. 2005;23:9441-9442.
Patients With 3 Drugs (%)
0
Med
ian
OS
(m
on
ths)
10 20 30 40 50 60 70 80
13
14
15
16
17
18
19
20
2122
12
5-FU/IRI vs FOLFOXIRI: Falcone et al
N = 244
FOLFOXIRI
5-FU/Iri5-FU/IriDouillardDouillard
Falcone ASCO 2007Falcone ASCO 2007
R
A
N
D
O
M
I
Z
E
Metastatic Colorectal Cancer
Efficacy
5-FU/IRI
N=122
FOLFOXIRI
N=122
P-value
Response rate (%)
41% 66% ?
PFS (mos) 6.9
(BICC = 8.3)
9.9 0.0009
OS (mos) 16.7
(BICC = 23)
23.6 0.042
Falcone ASCO 2007
Availability of All Cytotoxic Agents and Survival
Courtesy of Dr. Goldberg, adapted from Grothey A and Sargent D. J Clin Oncol. 2005;23:9441-9442.
Patients With 3 Drugs (%)
0
Med
ian
OS
(m
on
ths)
10 20 30 40 50 60 70 80
13
14
15
16
17
18
19
20
2122
12
*FOLFOXIRI
FU/IRI(42 pts)
FOLFOXIRI(39 pts)
R0 12%*(5 pts)
36%*(14 pts)
* p=0.017
Post-ChemoRx Resections(patients with liver mts only)
Falcone ASCO 2007
Phase III Trial With Bevacizumab Therapy in First-Line MCRC
Bolus IFL + BV(n = 403)
5-FU/LV + BV(n = 110)
Bolus IFL + placebo(n = 412)
RR
AA
NN
DD
OO
MM
II
ZZ
EE
Untreated
MCRC
Hurwitz H, et al. N Engl J Med 2004;350:2235–42
Phase III Trial of Bevacizumab in First-Line MCRC
IFL + Placebo (n=411)
IFL + Bevacizumab
(n=402) P Value
ORR (%)
CR
PR
35
2.2
32.5
45
3.7
41.2
0.0036
Hurwitz H, et al. N Engl J Med 2004;350:2235–42
Median PFS (months)IFL + placebo: 6.2 (95% CI: 5.6–7.7)IFL + Bevacizumab: 10.6 (95% CI: 9.0–1.0)HR=0.54 (95% CI: 0.45–0.66) p<0.001
Pro
bab
ilit
y o
f b
ein
g p
rog
ress
ion
-fre
e 1.0
0.8
0.6
0.4
0.2
00 10 20 30
PFS (months)
6.2 10.6
IFL + Bevacizumab
IFL + placebo
Phase III trial : PFS
Hurwitz H, et al. N Engl J Med 2004;350:2335–42
Median survival (months)IFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + Bevacizumab: 20.3 (95% CI: 18.5–24.2)HR=0.66 (95% CI: 0.54–0.81) p<0.001
Pro
bab
ilit
y o
f su
rviv
al
1.0
0.8
0.6
0.4
0.2
00 10 20 30 40
Survival (months)
IFL + Bevacizumab
IFL + placebo
15.6 20.3
Hurwitz H, et al. N Engl J Med 2004;350:2335–42
Phase III trial : Survival
FOLFIRI(n=144)
RmIFL
(n=141)
XELIRI(n=145)
Feb 2003 – April 2004
Initial design
n=430
FOLFIRI+Bev.
mIFL+Bev.
(n=60)
(n=57)
May 2004 – Dec 2004n=117
Primary endpoint: PFS
Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design
Protocol amended due
to approval of bevacizumab
Amended design
R
* Celecoxib data not shownFuchs et al, ASCO 2007
BICC Efficacy in 430 Patients
mIFL CapeIRI FOLFIRI P-value
Response rate (%)
43.3 38.6 47.2 N.S.
PFS (mos) 6.0 5.7 8.2 0.01
OS (mos) 17.6 18.9 23.1 N.S.
Fuchs et al, ASCO 2007
Adverse EventGrade 3-4
FOLFIRIn = 137
(%)
m-IFLn = 137
(%)
CapeIRI n = 141
(%)
Nausea 8.8 7.3 18.4
Vomiting 8.8 7.3 15.6
Diarrhea 13.9 19 47.5
Dehydration 5.8 7.3 19.1
Neutropenia 43.1 40.9 31.9
Febrile neutropenia 3.6 12.4 7.1
Hand-foot syndrome 0 0 9.9
60-day mortality 3.6 5.1 3.5
Period 1: Grade 3-4 AEs
Fuchs et al, ASCO 2007
Period 2: Efficacy
mIFL + Bev
N=60
FOLFIRI + Bev
N=57
P-value
Response rate (%)
? ? ?
PFS (mos) 8.3 11.2 0.28
OS (mos) 19.2 Not reached 0.01
Fuchs et al, ASCO 2007
Progression Free SurvivalP
rop
ort
ion
of
Su
bje
cts
Wh
o
Did
No
t P
rog
ress
Regimen PFS (Mos) P Value
FOLFIRI + BEV 11.2 --
mIFL + BEV
8.3 0.28
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 10 20 30
Time to Progression (months)
FOLFIRI + Bevacizumab
mIFL + Bevacizumab
Fuchs et al, ASCO 2007
Overall Survival
Survival Time (months)
RegimenMedian OS (Months) 1 Year P Value
FOLFIRI+ BEV Not Reached 87% --
mIFL + BEV 19.2 61% 0.01
Pro
po
rtio
n o
f S
ub
ject
s W
ho
Su
rviv
ed
FOLFIRI + Bevacizumab
mIFL + Bevacizumab
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 10 20 4030
Fuchs et al, ASCO 2007
E3200: Phase III Trial of Bevacizumab in Second-Line Metastatic CRC
FOLFOX4
BV monotherap
y
FOLFOX4 + BV
Previously IFL
Treated Metastati
c CRC(n=880)
Giantonio, ASCO 2005
E3200: Efficacy
4.8P < 0.0001 vs. BV
3.0%9.2%21.8%P < 0.0001 vs.
FOLFOX
RR
2.77.2P < 0.0001 vs.
FOLFOX
PFS (months)
10.2
230
Bevacizumab
10.8
12.9P = 0.0018 vs.
FOLFOX
OS
(months)
271271
FOLFOX4FOLFOX4 + bevacizumab
Giantonio BJ et al. ASCO 2005
Phase III Trial of Bevacizumab With Oxaliplatin-Based Therapy in CRC
Primary end point:
PFS
Previously untreated MCRC
(N=1600)
XELOX
FOLFOX4
+ Placebo
+ Placebo
+ Bevacizumab(7.5 mg/kg, q3w)
+ Bevacizumab(5 mg/kg, q2w)
Saltz L, et al. ASCO 2007
Efficacy
XELOX/FOLFOX
N=701
XELOX/FOLFOX + bev
N=699
P-value
Response rate (%) 49% 47% 0.99
PFS (mos) 8.0 9.4 0.0023
OS (mos) 19.9 21.3 0.076
Saltz L, et al. GI ASCO 2007
Overall survival
HR=0.89 (97.5% CI 0.76–1.03)
p=0.0769
XELOX / FOLFOX-4 + bevacizumab n=699 (420 events)
XELOX / FOLFOX-4 + placebo n=701 (455 events)
1.0
0.8
0.6
0.4
0.2
0
Months
Su
rviv
al e
stim
ate
0 6 12 18 24 30 36
19.9 21.3
Saltz L, et al. ASCO 2007
Cetuximab in Colorectal Cancer “Bond Trial”
Irinotecan pre-treated EGF-R positive Metastatic CRC
Cetuximab and Irinotecan218 patients
Cetuximab 111 patients
* 577 patients screened 329 patients included in a 2:1 randomization
PD
Cunningham et al. NEJM 2004;351:337-345
Cetuximab Combination Therapy “BOND” Trial
IRI/Cx Cx Assessment (n=218) (n=111) P-value
Response Rate 22.9% 10.8% 0.007
TTP 4.1 mo. 1.5 mo.<0.001 (Median)
Survival (Median) 8.6 mo. 6.9 mo. 0.48
Cunningham et al. NEJM 2004;351:337-345
Cetuximab may circumvent irinotecan resistance
Correlation Between Response Rate and Prior Treatment
SubgroupsCombination
n/N (%)Monotherapy
n/N (%)
Prior regimens
1 7/41 (17.1) 5/27 (18.5)
2 20/79 (25.3) 5/41 (12.2)
≥3 23/98 (23.5) 2/43 (4.7)
Prior oxaliplatin
yes 30/135 (22.2) 6/71 (8.5)
no 20/83 (24.1) 6/40 (15.0)
The BOND II Trial
RANDOMI
Z E
Bevacizumab+
Cetuximab
Bevacizumab+
Cetuximab+
Irinotecan
CRC patients who progressed
on irinotecan(any line)
Saltz et al, ASCO 2005
The BOND II Trial
• Best response on study
– CBI (n= 41) PR = 37%
– CB (n=40) PR = 20%
• Median time to tumor progression:
– Cetux/Bev/IRI 7.9 months
– Cetux/Bev 5.6 months
Saltz et al, ASCO 2005
CALGB 80405 Intergroup Trial
mFOLFOX6or
FOLFIRI
Bevacizumab
Cetuximab
Bevacizumab + Cetuximab
R
A
N
D
O
M
I
Z
E
Panitumumab Phase III Trial in First Line Metastatic CRC: PACCE
RRAANNDDOOMMII
Z Z E E
FOLFOX or FOLFIRI+
Bevacizumab+
Panitumumab
FOLFOX or FOLFIRI+
Bevacizumab
Previously untreated CRC
patientsN=1000
PACCE: Panitumumab Advanced Colorectal Cancer Evaluation
Press release reported lack of benefit in experimental arm
First Line Trials: Caveats for Survival as Endpoint
Randomization
Drug A
Drug A + B
Crossover to B not encouraged
Classic
Randomization
Drug A
Drug A + B
Crossover to B mandatory
Practical
The FOCUS Trail
Drug A until it fails… …then B until it fails“staged single
agents”A
Drug A until it fails……then add drug B until both fail
“staged
combination”B
Drugs A + B together until both fail“1st-line
combination”C
A: FU until it fails, then change to Ir
“3rd drug” salvage
OxCap
OxCap
IrCap
OxCap
IrCap
B(ir): FU until it fails, then add Ir
B(ox): FU until it fails, then add Ox
C(ir): FU+Ir from the start, until it fails
C(ox): FU+Ox from the start, until it fails
700
350
350
350
350
2100patients
Focus Design
Seymour et al ASCO 2005
Overall survival
Plan First 2 drugs schedule Median OS
A FU then Ir 13.9
B(ir)
B(ox)
FU then FU/Ir
FU then FU/Ox
14.8
15.2
C(ir)
C(ox)
1st-line FU/Ir
1st-line FU/Ox
16.3
15.2
Seymour et al ASCO 2005
FOCUS Summary
• Use of sequential chemotherapy, with deferred use
of combinations, appears as effective as using the
combination upfront; HOWEVER…
• Sequential single agents appears to be inferior than
single agent followed by an appropriate combination
• Questions remain regarding exposure to all agents
• Not all agents should be used alone
CAIRO: Trial Profile
Arm A Arm B
Randomize
capecitabineN=397
capecitabine +oxaliplatin
N=143 (36%)
irinotecanN=251 (62%)
capecitabine +oxaliplatin
N=213 (53%)
capecitabine +irinotecan
N=398
1st line
2nd line
3rd line
Courtesy of Punt et al, ASCO 2007
Median Overall Survival
Combination treatment 17.4 months (15.2-19.2)
----------- Sequential treatment 16.3 months (14.3-18.2)
p = 0.33
Courtesy of Punt et al, ASCO 2007
Who, What, How Definitions
• Intense therapy:
– Implies early use of more complex combinations
– Is not the same as piling all active drugs together
• Minimal therapy:
– Seeks to minimize toxicity and perhaps cost
– It is not the same as sequential monotherapy
– It is not minimalist therapy
Who, What, How
• Who should get upfront intense therapy?
– Depends on what you call intense therapy!
– Patients who may become resectable with a good
response
– Patients whose quality of life may improve with a
tumor response
– Patients who are unlikely to get second and third
line treatment regimens (e.g., aggressive tumors)
Who, What, How
• Who should get upfront minimal therapy?
– Reserved for patients with little hope for a
curative surgery
– Patients who have relatively indolent disease, and
who can expect to receive additional lines of
therapy
– Patients with good quality of life who are not
interested in trading it for improvements in the
therapy’s efficacy
Chemotherapy for CRCSummary
• Doublets are more active than single agents, and
triplets may be even better
• Use of combinations of agents, in some sequence,
results in better response rates, resection rates, time
to progression, and overall survival
• However, the agents do not all need to be used
upfront
• Judicious use of combination therapy, in an
appropriate sequence, is indicated for most patients
How Should We Use the Available Drugs
• Good activity by itself– 5-FU/LV– Capecitabine– UFT– Irinotecan– Raltitrexed
• Better used in combination– Oxaliplatin
• FOLFOX / XELOX• IROX
– Bevacizumab• 5-FU • Oxaliplatin• Irinotecan• Cetuximab
– Cetuximab• Irinotecan• FOLFOX / XELOX
– Panitumumab?
The Building Block Strategy
5-FU + LV
5-FU + Oxaliplatin
Irinotecan + Cetuximab
Capecitabine
Irin
ote
can
5-F
U +
B
ev
aciz
um
ab
Capecitabine + OxaliplatinPanitumumab
Conclusion
• Treatment objectives are often different
• Patients are different
• Tumor biology and behavior is variable1
• Why should the treatment be the same ?
• We desperately need studies to learn how to match
the correct treatment with the appropriate patient
1O’Connell et al Abst. 4009, ASCO 2007