Chemotherapy for
Metastatic Colon Cancer
Scott Berry
Sunnybrook Health Sciences Centre
Where Were We Until
2000?
O
F
HN
O
N
H
5-FU
bevacizumab
oxaliplatin
NH2
O
C
FOLFIRI
Pt
NH2
O
C
O
cetuximab
Panitumumab
PTK 787
FOLFOX
irinotecan
CH3
CH2
N
O
N
N
C
O
IFL
Capecitabine
O
N
O
HO
O
CH2C H3
OS for 1st line Combinations
5-FU/LV (Saltz)
5-FU/LV (Douillard)
5-FU/LV (de Gramont)
IFL (Goldberg)
IFL (Saltz)
FOLFIRI (Douillard)
FOLFOX (de Gramont)
FOLFOX (Goldberg)
IFL+ Bevacizumab
0
5
10
15
Median OS (months)
20
25
Overview/Objectives
•
Review key evidence from randomized trials evaluating
the chemotherapies and chemotherapy strategies that
have emerged for metastatic colorectal cancer looking
at both:
• Efficacy
• Safety
•
Key Strategies and Questions:
•
•
•
•
•
Which doublet should be used?
? Should we be using triplet therapy
Can capecitabine replace infusional 5FU in doublets?
Can sequential monotherapy replace initial doublet therapy?
Can toxicity be reduced and efficacy maintained with “on/off”
chemotherpay strategies?
Chemotherapy
Case
• 50 yo woman with no history of medical
problems presents with bilobar liver and
bilateral lung metastases
– ECOG 1 – some RUQ pain and cough
• What is the optimal chemotherapy choice for
her?
•
•
•
•
•
•
CAPECITABINE
FOLFOX
FOLFIRI
CAPE IRI
CAPE OX
FOLFOXIRI
Efficacy of Chemotherapy in FirstLine CRC: Phase III Trial Results
Regimen
RR (%)
Median OS
(mo)
5-FU/LV
21
12.6
IFL (Saltz trial)
39 (P<0.001)
14.8 (P=0.04)
5-FU/LV
22
14.1
FOLFIRI (Douillard trial)
35 (P<0.005)
17.4 (P=0.031)
5-FU/LV
22
14.7
FOLFOX4 (de Gramont trial)
51 (P=0.0001)
16.2 (P=0.12)
Saltz et al. N Engl J Med. 2000;343:905; Douillard et al. Lancet. 2000;355:1041;
de Gramont et al. J Clin Oncol. 2000;18:2938
•
•
•
•
•
•
CAPECITABINE
FOLFOX
FOLFIRI
CAPE IRI
CAPE OX
FOLFOXIRI
Phase III Intergroup N9741 Study
(Goldberg JCO, 2004)
R
A
N
D
O
M
I
Z
A
T
I
O
N
IFL
FOLFOX 4
Irinotecan + Oxaliplatin
Phase II Sequential,
Randomized CrossoverStudy
FOLFIRI
FOLFOX 6
Tournigand et al JCO 2004
N9741/Tournigand Trial: Results
N9741
Tournigand
IFL
FOL
FOX
Pvalue
FOL FOL
PFIRI FOX value
RR
%
31
45
.03
56
54
.26
TTP
mos
6.9
8.7
.009
8.5
8.0
.26
OS
mos
15
19.5
.0002
21.5 20.6
.99
Tournigand Trial: Results
Curative Surgery Rate: 22% FOLFOX , 9% FOLFIRI
Tournigand
Toxicity grade >3
%
40
P>0.05 for
Comparisons marked
by arrows
FOLFIRI
34%
FOLFOX
30
20
14%
Alopecia
Any grade
60% vs 28%
13%
11%
10
0%
0
10%
7%
3%
3%
3%
60-day
Mortality:
4% vs 3%
Combination Chemotherapy Summary
• Combination chemotherapy with FOLFIRI or
FOLFOX are both acceptable first line
chemotherapy regimens for people with
metastatic colorectal cancer
• Follow by alternate combination (or single agent
Irinotecan after FOLFOX)
• Considerations:
– Toxicity profile
– ? Considering surgery : FOLFOX based on “circumstantial” evidence
•
•
•
•
•
•
CAPECITABINE
FOLFOX
FOLFIRI
CAPE IRI
CAPE OX
FOLFOXIRI
Overall survival
Estimated probability
Capecitabine (n=603)
5-FU/LV (n=604)
1.0
0.8
0.6
0.4
0.2
13.1
13.1
0
0
5
10
15
20
Time (months)
25
30
Integrated CRC
What About Capecitabine
As a Partner?
Capecitabine + Irinotecan
BICC-C study
n=430
1st line
mCRC
FOLFIRI +/- celecoxib
mIFL +/- celecoxib
CAPIRI (Cape 1000mg/m2 d1-14) +/- celecoxib
FOLFIRI
mIFL
CAPIRI
Median OS (mos)
23.1
17.6 (p=0.1)
18.9 (p=0.42)
Median PFS (mos)
8.2
6.0 (p=0.01)
5.7 (p=0.01)
g3/4 nausea
6.6
6.6
18.4
g3/4 vomiting
5.8
6.6
15.6
g3/4 diarrhea
13.9
16.8
47.5
g3/4 dehydration
5.8
6.6
19.1
0
0
9.9
3.6
12.4
7.1
G3/4 HFS
Febrile neutropenia
Slide Courtesy D Jonker from data presented at ASCO 2007
EORTC 40015 study
n=85
1st line
CRC
FOLFIRI +/- celecoxib
CAPIRI (Cape 1000mg/m2 bid x14d)+/- celecoxib
FOLFIRI
CAPIRI
Req dose adjustment (%)
33%
53%
g3/4 diarrhea
13%
37%
5 (10w)
3 (9w)
Dose intensity irinotecan
85%
83%
Median OS (mos)
19.9
14.8
Median PFS (mos)
9.6
5.9
Median number cycles
Celecoxib vs Placebo : No Survival difference
Slide Courtesy D Jonker
What About Capecitabine
As a Partner?
Capecitabine + Oxaliplatin
Capecitabine + Oxaliplatin
Randomized Trials : Efficacy
First
Line
Regimen
RR (%)
Median OS
(mo)
Capecitabine (1000 bid) +
42
19.9
Ox (130 q 3wks)
46
20.5 (p=NS)
FOLFOX 6 (oxali 100 q 2wks)
Non-Inferior
(Ducreux ASCO 2007 N=306)
Capecitabine + Ox
NR
FOLFOX 4
19.6
19.8 (p=NS)
(Cassidy ASCO 2007 N=2034)
Second
Line
Capecitabine+ Ox
15
13.2
FOLFOX 4
12
12.8 (p=NS)
(Rothenberg ASCO 2007 N=
627)
Capecitabine + Oxaliplatin Randomized Trials : Toxicity
First
Line
Regimen
Toxicity
Capecitabine (1000 bid) + Ox
(130 q 3wks)
FOLFOX arm had significantly more Gr
3/4:
FOLFOX 6 (oxali 100 q 2wks)
Neuropathy (25 v 11%), Feb Neut (6 v 0%)
(Ducreux ASCO 2007 N=306)
Capecitabine + Ox
FOLFOX arm had more Gr 3/4:
FOLFOX 4
Feb Neut (5 v <2%)
(Cassidy ASCO 2007 N=2034)
CapeOx arm had more Gr 3/4:
Diarrhea (20 v 12%) and HFS (6 v 1%)
Second
Line
Capecitabine + Ox
FOLFOX arm had more Gr 3/4:
FOLFOX 4
Feb Neut
(Rothenberg ASCO 2007 N= 627)
CapeOx arm had more Gr 3/4:
Diarrhea (20 v 7) and HFS (4 v <2%)
Can Capecitabine Replace Infusional 5FU in
mCRC?
• Capecitabine and Irinotecan
– At doses studied CapeIri is more toxic and less effective
than FOLFIRI
• Capecitabine and Oxaliplatin
– CapeOx has same efficacy as FOLFOX
– Differential toxicity profile between CapeOx and FOLFOX
•
•
•
•
•
•
CAPECITABINE
FOLFOX
FOLFIRI
CAPE IRI
CAPE OX
FOLFOXIRI
Triplet Therapy
5-FU/IRI vs FOLFOXIRI:
Falcone et al
N = 244
5-FU/Iri
Douillard
Randomization
FOLFOXIRI
Slide Courtesy of R Goldberg
FOLFOXIRI Schedule
Day 1
Day 2
Day 3
CPT-11
165 mg/m2
Oxaliplatin
85 mg/m2
L-LV
200 mg/m2
1 hour
2 hours
5FU flat continuous infusion
3200mg/m2
48 hours
Repeated every 14 days
Slide Courtesy of R Goldberg
Efficacy
Response
rate (%)
PFS (mos)
OS (mos)
5-FU/IRI
N=122
41%
FOLFOXIRI
N=122
66%
P-value
6.9
(BICC = 8.3)
16.7
9.9
0.0009
23.6
0.042
?
Slide Courtesy of R Goldberg
Post-ChemoRx Resections
(patients with liver mts only)
FU/IRI
(42 pts)
R0
12%*
(5 pts)
FOLFOXIRI
(39 pts)
36%*
(14 pts)
* p=0.017
Slide Courtesy of R Goldberg
Grade 3-4 Toxicity
100%
100%
75%
FOLFIRI
(N=122)
FOLFOXIRI
(N=122)
75%
p =0.0006
50%
50%
50%
5
28%
25%
25%
3% 5%
1% 2%
1% 3%
20%
12%
0%
20%
2%
Neutropenia Febrile Neutropenia Thrombocytopenia
Anemia
7%
3% 5%
3% 6%
Stomatitis
Asthenia Neurotoxicity
0%
0%
Diarrhea
Vomiting
Slide Courtesy of R Goldberg
Survival improves with availability
of three active drugs
*
FOLFOXIRI
P=0.0001
Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442.

Is FOLFOXIRI more active than 5-FU/IRI?
Yes, including better resection rates


But is comparator arm inferior?
More toxic
Monotherapy
Overall survival
Estimated probability
Capecitabine (n=603)
5-FU/LV (n=604)
1.0
0.8
0.6
0.4
0.2
13.1
13.1
0
0
5
10
15
20
Time (months)
25
30
Integrated CRC
Monotherapy
versus
doublets
• ? Have 3 active chemo agents in mCRC
• Lead with combination
• ? Can we use agents sequentially and maintain
efficacy and reduce toxicity
• FOCUS and CAIRO
– Do both have fatal flaws?
FOCUS
Lancet, 2008
FOCUS UK MRC CR08
2,135 Untreated Stage IV patients
R
A
N
D
O
M
I
S
A
T
I
O
N
A: 5 FU/LV (de Gramont)
IRI
B: 5 FU/LV (de Gramont)
FOLFOX or
FOLFIRI
C: FOLFOX vs FOLFIRI
FOCUS UK MRC CR08
• Breaks allowed
– Not before 3 mos
– Only 4 weeks in 2nd 3 mos
– After that – allowed with re-start of previous
regimen as long as progression hadn’t occurred
within 12 weeks of stopping
FOCUS UK MRC CR08
• Up to Dec 02 , recommended salvage in all
groups Infusional 5FU and Mit-C
• Since Dec 02, "balanced salvage" with
CapOx or CapIri
• Primary Endpoint: Survival
Survival
OS (mos)
5FU TO IRI
13.9
5FU TO FOLFOX
15.2
5FU TO FOLFIRI
15.0
FOLFOX
15.4
FOLFIRI
16.7
(p=0.01)
Table 4
FOCUS
QOL
• Mean overall QOL : varied little between arms
and regimens
• In particular, no differences seen at 3 and 6 mos
FOCUS
• Conclude that sequential strategy is a valid
option
• Median Survivals of all arms inferior to FOLFOX
arm of N9741 and both arms of Tournigand trial
• ? Seeing an effect of restricting access to all 3
drugs
Percentage of Patients Receiving All
3 Active Drugs
OS
(mos)
A
B
5FU TO IRI
5FU TO
FOLFOX
5FU TO
FOLFIRI
16%
19%
FOLFOX
33%
C
FOLFIRI
FOCUS
Grothey, JCO, 2004
CAIRO
Randomized study of sequential versus
combination chemotherapy with capecitabine,
irinotecan and oxaliplatin in advanced colorectal
cancer
a study of the Dutch Colorectal Cancer Group (DCCG)
CJA Punt, M Koopman, J Douma, J Wals, AH Honkoop
FLG Erdkamp, RS de Jong, CJ Rodenburg,
L Mol, NF Antonini
ASCO 2007
CAIRO study
CKTO 2002-07
Randomize
Arm A
Arm B
capecitabine
capecitabine +
irinotecan
2nd line
irinotecan
capecitabine +
oxaliplatin
3rd line
capecitabine +
oxaliplatin
1st
line
Dose/schedule of drugs
all cycles given 3 weekly
•
•
•
•
Capecitabine monotherapy:
1250 mg/m2 b.i.d. day 1-14
Irinotecan monotherapy: 350 mg/m2 day 1
CAPIRI1: capecitabine 1000 mg/m2 b.i.d. day 1-14 +
irinotecan 250 mg/m2 day 1
CAPOX2: capecitabine 1000 mg/m2 b.i.d. day 1-14 +
oxaliplatin 130 mg/m2 day 1
Rea et al. Ann Oncol 2005
2 Borner et al. J Clin Oncol 2002
1
Trial profile
Randomize
Arm A
1st
2nd
Arm B
line
capecitabine
N=397
capecitabine +
irinotecan
N=398
line
irinotecan
N=251 (62%)
capecitabine +
oxaliplatin
N=213 (53%)
3rd line
capecitabine +
oxaliplatin
N=143 (36%)
Median overall survival
Combination treatment 17.4 months (15.2-19.2)
----------- Sequential treatment 16.3 months (14.3-18.2)
p=
0.33
Efficacy results
Sequential
N=401
Combination
N=402
p value
Median overall survival (months)
16.3
17.4
0.33
Hazard ratio for death
1.08
One-year survival rate (%)
64
67
Median PFS (months) 1st line
5.8
7.8
Overall response rate (CR + PR)*
1st line
2nd line
3rd line
77 (20%)
23 (10%)
5 (4%)
139 (41%)
24 (12%)
-
Disease control rate (CR + PR + SD)*
1st line
2nd line
3rd line
280 (74%)
162 (71%)
72 (57%)
297 (87%)
121 (63%)
* Percentages are based on patients evaluable for response
0.0002
Grade 3-4 toxicities in first line
Arm A
capecitabine
N = 397
Arm B
capiri
N = 398
p value
Hand-foot syndrome
12%
6%
0.002
Diarrhea
11%
26%
<0.001
Nausea
4%
10%
0.004
Vomiting
3%
9%
0.0002
Stomatitis
<1%
2%
0.16
Thrombosis/embolism *
7%
10%
0.20
Febrile neutropenia
<1%
7%
<0.001
Toxicity
* All grades
Quality of life
•
•
•
Participation to this part of the study was proposed to the
first 620 patients entered in the study (QLQ-C30
questionnaire of the EORTC)
403 patients were evaluable for quality of life
Quality of life scores were comparable between the two
arms, except for diarrhoea which was reported more
frequently in combination treatment
Conclusions
•
•
•
•
Combination treatment is not superior in terms of efficacy to sequential
treatment in patients with advanced colorectal cancer
Our results on median overall survival for sequential treatment are the
highest reported when a fluoropyrimidine is administered as
monotherapy in 1st line
Sequential treatment is a useful alternative for combination treatment
Our results may be useful for strategies in which chemotherapy is
combined with targeted agents
What about use of CapeIri?
62
Back to CAIRO
• PFS Capeiri in CAIRO similar to FOLFIRI in BICC-C
– But OS of 17 mos is less than we’ve come to expect
in sequential doublets
– Cross trial comparisons
– CapeIri in CAIRO better tolerated than CapeIri in
BICC-C or EORTC trial except for high rates of
diarrhea (~ double that seen with FOLFIRI in
Tournigand or BICC-C)
• Would Combination arm in CAIRO have done better if
FOLFIRI used?
– No one knows.
63
? Reasons for Results
• ? Geographic differences in capecitabine metabolism
– Similar results in Europe
• ? Celecoxib
– Results not published for BICC-C
• ? Different dose of cape do better
– Maybe but not used in this trial
64
Summary
• Both CAIRO and FOCUS validate a sequential
approach within the context of their study parameters
• ? Would they have done so if FOCUS had allowed
better access to all 3 chemo drugs and CAIRO had
used FOLFIRI?
65
Is Less Chemo More?
Case
• 50 yo woman with no history of medical
problems presents with bilobar liver and
bilateral lung metastases
– ECOG 1 – some RUQ pain and cough
She agrees to chemotherapy but asks if there is
anyway she can take a break during chemo
without reducing the benefits of chemo?
Which of the following strategies has been shown
to reduce toxicity without impacting on efficacy?
• Induction of FOLFOX for 3 mos followed by
infusional 5FU maintanence then reintroduce
FOLFOX
• Induction of FOLFOX for 3 mos followed by
no maintanence (complete chemo break)
then reintroduce FOLFOX
• FOLFIRI on for 2 mos, off for 2 mos
Stop and Go concept - OPTIMOX1
FOLFOX4
R
6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7
620 pts
Cum. Oxali
(%)
FOLFOX4
RR
58.5
PFS
9.0
DDC
9.0
OS
19.3
G3/4 NTox
17.9
780
1560
FOLFOX7
58.3
8.7
10.6
21.2
13.3
Primary
endpoint
Tournigand et al, JCO 2006
OPTIMOX2, a large randomized phase II study of
maintenance therapy or chemotherapy-free intervals
(CFI) after FOLFOX in patients with metastatic
colorectal cancer (MRC).
A GERCOR study.
F. Maindrault-Gœbel, G. LLedo, B. Chibaudel,
L. Mineur, T. André, M. Bennamoun, M. Mabro,
P.Artru, C. Louvet, A. de Gramont
OPTIMOX Studies
FOLFOX 4 until TF
OPTIMOX-1
FOLFOX 7
FOLFOX 7
sLV5FU2
mFOLFOX 7
mFOLFOX 7
sLV5FU2
OPTIMOX-2
mFOLFOX 7
mFOLFOX 7
CFI
Baseline Progression
T size
Chemotherapy-free Interval
t
FOLFOX
FOLFOX
Progression
Baseline
progression
Progression
at reintroduction
Duration of Disease Control
DDC = PFS 1 + PFS 2 (if no PD)
T size
PFS 1
PFS 2
t
FOLFOX
FOLFOX
Progression
ASCO 2001, 146a
Baseline
progression
Progression
at reintroduction
Neuropathy
Optimox 1
Optimox 2
Grade
1
70.7 %
2
18.1 %
3
0 %
Grade
1
70.8 %
2
16.5 %
3
0 %
2 months after
FOLFOX
Grade
1
8%
2
21.2 %
3
2%
Grade
1
6.8 %
2
15.5 %
3
3.9 %
After the first
reintroduction
Grade
1
29.4 %
2
35.3 %
3
5.9 %
Grade
1
36.8 %
2
19.2 %
3
7%
During C1-C6
Chemotherapy-free Interval
C h e m o th e ra p y-fre e in te rv a l
1 .0
y
t
i
l
i
b
a
b
o
r
P
0 .8
O P T I M O X 2 m e d ian 1 7 we e ks
R 0 s urg e ry e xc lud e d
0 .6
0 .4
0 .2
0 .0
0
10
20
30
40
50
weeks
60
70
80
90
100
Duration of Disease Control
D u ra tio n o f D is e a s e C o n tro l
1 .0
y
t
i
l
i
b
a
b
o
r
P
O P T I M O X 1 m e d ian 5 2 we e ks
0 .8
O P T I M O X 2 m e d ian 3 9 we e ks
0 .6
p = 0 .3 9
0 .4
0 .2
0 .0
0
10
20
30
40
50
weeks
60
70
80
90
100
Overall Survival
O v e ra ll S u rv iv a l
1 .0
y
t
i
l
i
b
a
b
o
r
P
O P T I M O X 1 m e d ian 2 6 m o nths
0 .8
O P T I M O X 2 m e d ian 1 9 m o nths
0 .6
p = 0 .0 5 4 9
0 .4
0 .2
0 .0
0
10
20
30
m o n th s
40
50
Alternating vs continuous FOLFIRI in advanced
colorectal cancer (ACC):
a randomized GISCAD trial
Roberto Labianca
Ospedali Riuniti – Bergamo, Italy
Floriani I, Cortesi E, Isa L, Zaniboni A, Marangolo M, Frontini L,
Barni S, Beretta GD, Sobrero A
GISCAD-Trial: Design
N=336
FOLFIRI
R
Evaluation
4 mos
• Primary endpoint: OS
PFS
Median f-up: 30 m
Median time to PD:
Arm A 6.2 m
Arm B 6.5 m
Cox analysis (after adjustment for gender, age and site): HR: 1.01 (0.78-1.27)
OS
Median f-up: 30 m
Median survival time:
Arm A
16.9 m
Arm B
17.6 m
Cox analysis (after adjustment for gender, age and site): HR: 1.03 (0.78-1.35)
Toxicity
• Grade 3/4 toxicities similar in both arms
– This paradigm of toxicity measurement is not
appropriate for this type of trial
• No QOL analysis
Summary
• GISCAD
– Equivalent DFS, OS, toxicity
– ? Rationale clinical strategy
• OPTIMOX2
• ? Longer induction needed
• ? Shorter break before re-introduction
• ? Different maintenance strategy
From OPTIMOX to DREAM
OPTIMOX-1
OPTIMOX-2
DREAM
Efficacy =
Toxicity
Efficacy decresed
Toxicity =
Bevacizumab
Erlotinib
Bevacizumab