Chemotherapy for Metastatic Colon Cancer
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Chemotherapy for Chemotherapy for Metastatic Colon CancerMetastatic Colon Cancer
Scott BerryScott Berry
Sunnybrook Health Sciences CentreSunnybrook Health Sciences Centre
Where Were We Until 2000?
NH
HN
O
O
F
5-FU5-FU
FOLFOX
FOLFIRI
IFL
irinotecan
N NC
O
O N
N O
O
O
C 2H
O C 2H
C 3H
H C 3H
oxaliplatinNHNH22
NHNH22
PtPt
OO
OO CC
OO
CC
bevacizumab
cetuximab
PTK 787
CapecitabineCapecitabine
PanitumumabPanitumumab
OS for 1OS for 1stst line Combinations 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 20 25Median OS (months)
Overview/ObjectivesOverview/Objectives• Review key evidence from randomized trials evaluating the Review key evidence from randomized trials evaluating the
chemotherapies and chemotherapy strategies that have chemotherapies and chemotherapy strategies that have emerged for metastatic colorectal cancer looking at both:emerged for metastatic colorectal cancer looking at both:• EfficacyEfficacy• SafetySafety
• Key Strategies and Questions:Key Strategies and Questions:• Which doublet should be used?Which doublet should be used?• ? Should we be using triplet therapy? Should we be using triplet therapy• Can capecitabine replace infusional 5FU in doublets?Can capecitabine replace infusional 5FU in doublets?• Can sequential monotherapy replace initial doublet therapy?Can sequential monotherapy replace initial doublet therapy?• Can toxicity be reduced and efficacy maintained with “on/off” Can toxicity be reduced and efficacy maintained with “on/off”
chemotherpay strategies? 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 First-Line CRC: Phase III Trial Results
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
Regimen RR (%)Median OS (mo)
5-FU/LV
IFL (Saltz trial)
21
39 (P<0.001)
12.6
14.8 (P=0.04)
5-FU/LV
FOLFIRI (Douillard trial)
22
35 (P<0.005)
14.1
17.4 (P=0.031)
5-FU/LV
FOLFOX4 (de Gramont trial)
22
51 (P=0.0001)
14.7
16.2 (P=0.12)
• CAPECITABINE
• FOLFOX
• FOLFIRI
• CAPE IRI
• CAPE OX
• FOLFOXIRI
Phase III Intergroup N9741 Study(Goldberg JCO, 2004)
RRAANNDDOOMMII
Z Z AATTIIOON N
Irinotecan + Oxaliplatin Irinotecan + Oxaliplatin
IFLIFL
FOLFOX 4FOLFOX 4
Phase II Sequential, Randomized CrossoverStudy
Tournigand et al JCO 2004
FOLFIRIFOLFIRI
FOLFOX 6FOLFOX 6
N9741/Tournigand Trial: ResultsN9741 Tournigand
IFL FOLFOX
P-value
FOLFIRI
FOLFOX
P-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 Curative Surgery Rate: 22% FOLFOX , 9% FOLFIRI
FOLFIRIFOLFIRI
FOLFOXFOLFOX
00
1010
2020
3030
F. neu
tropen
ia
F. neu
tropen
ia
Nause
a
Nause
a
Vomiti
ng
Vomiti
ng
Diarrh
ea
Diarrh
ea
Pares
thes
ia
Pares
thes
ia
%
7%7%
13%13%
0%0%3%3%
14%14%
11%11% 10%10%
3%3% 3%3%
34%34%4040
TournigandTournigandToxicity Toxicity ggrade rade >>33
P>>0.05 for0.05 forComparisons marked Comparisons marked
by arrowsby arrows
AlopeciaAny grade 60% vs 28%
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
Integrated CRC
Capecitabine (n=603)
5-FU/LV (n=604)
13.1 13.1
0 5 10 15 20 25 30
Time (months)
Est
imat
ed p
rob
abil
ity 1.0
0.8
0.6
0.4
0.2
0
What About Capecitabine As a Partner?
Capecitabine + Irinotecan
BICC-C studyFOLFIRI +/- celecoxib
CAPIRI (Cape 1000mg/m2 d1-14) +/- celecoxib
n=430
1st line mCRC
mIFL +/- 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
G3/4 HFS 0 0 9.9
Febrile neutropenia 3.6 12.4 7.1
Slide Courtesy D Jonker from data presented at ASCO 2007Slide Courtesy D Jonker from data presented at ASCO 2007
EORTC 40015 studyFOLFIRI +/- celecoxib
CAPIRI (Cape 1000mg/m2 bid x14d)+/- celecoxib
n=85 1st line CRC
FOLFIRI CAPIRI
Req dose adjustment (%) 33% 53%
g3/4 diarrhea 13% 37%
Median number cycles 5 (10w) 3 (9w)
Dose intensity irinotecan 85% 83%
Median OS (mos) 19.9 14.8
Median PFS (mos) 9.6 5.9
Celecoxib vs Placebo : No Survival differenceCelecoxib vs Placebo : No Survival difference
Slide Courtesy D JonkerSlide Courtesy D Jonker
What About Capecitabine As a Partner?
Capecitabine + Oxaliplatin
Capecitabine + Oxaliplatin Randomized Trials : EfficacyRegimen RR (%)
Median OS (mo)
Capecitabine (1000 bid) +
Ox (130 q 3wks)
FOLFOX 6 (oxali 100 q 2wks)
(Ducreux ASCO 2007 N=306)
42
46
Non-Inferior
19.9
20.5 (p=NS)
Capecitabine + Ox
FOLFOX 4
(Cassidy ASCO 2007 N=2034)
NR 19.6
19.8 (p=NS)
Capecitabine+ Ox
FOLFOX 4
(Rothenberg ASCO 2007 N= 627)
15
12
13.2
12.8 (p=NS)SecondSecondLineLine
FirstFirstLineLine
Capecitabine + Oxaliplatin Randomized Trials : Toxicity
Regimen Toxicity
Capecitabine (1000 bid) + Ox (130 q 3wks)
FOLFOX 6 (oxali 100 q 2wks)
(Ducreux ASCO 2007 N=306)
FOLFOX arm had significantly more Gr 3/4:
Neuropathy (25 v 11%), Feb Neut (6 v 0%)
Capecitabine + Ox
FOLFOX 4
(Cassidy ASCO 2007 N=2034)
FOLFOX arm had more Gr 3/4:
Feb Neut (5 v <2%)
CapeOx arm had more Gr 3/4:
Diarrhea (20 v 12%) and HFS (6 v 1%)
Capecitabine + Ox
FOLFOX 4
(Rothenberg ASCO 2007 N= 627)
FOLFOX arm had more Gr 3/4:
Feb Neut
CapeOx arm had more Gr 3/4:
Diarrhea (20 v 7) and HFS (4 v <2%)
SecondSecondLineLine
FirstFirstLineLine
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: 5-FU/IRI vs FOLFOXIRI: Falcone et al Falcone et al
N = 244N = 244
FOLFOXIRI
5-FU/Iri
Douillard Randomization
Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg
FOLFOXIRI ScheduleFOLFOXIRI ScheduleFOLFOXIRI ScheduleFOLFOXIRI Schedule
5FU flat continuous infusion3200mg/m2
L-LV 200 mg/m2
Oxaliplatin 85 mg/m2
2 hours
Repeated every 14 days
CPT-11165 mg/m2
48 hours
Day 1 Day 2 Day 3
1 hour
Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg
EfficacyEfficacy
5-FU/IRI5-FU/IRI
N=122N=122FOLFOXIRIFOLFOXIRI
N=122N=122P-valueP-value
Response Response rate (%)rate (%)
41%41% 66%66% ??
PFS PFS (mos)(mos)
6.96.9
(BICC = (BICC = 8.3)8.3)
9.99.9 0.00090.0009
OS (mos)OS (mos) 16.716.7 23.623.6 0.0420.042
Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg
FU/IRIFU/IRI(42 pts)(42 pts)
FOLFOXIRIFOLFOXIRI(39 pts)(39 pts)
R0R0 12%*12%*(5 pts)(5 pts)
36%*36%*(14 pts)(14 pts)
* p=0.017
Post-ChemoRx Resections(patients with liver mts only)
Post-ChemoRx Resections(patients with liver mts only)
Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg
28%
3% 1% 1%
50%
5% 2% 3%
0%
25%
50%
75%
100%
Neutropenia Febrile Neutropenia Thrombocytopenia Anemia
FOLFIRI
FOLFOXIRI
5
Grade 3-4 ToxicityGrade 3-4 ToxicityGrade 3-4 ToxicityGrade 3-4 Toxicity
(N=122)
(N=122)
12%
2% 3% 3% 0%
20%
7% 5% 6%
20%
0%
25%
50%
75%
100%
Diarrhea Vomiting Stomatitis Asthenia Neurotoxicity
p =0.0006
Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg
Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442.
Survival improves with availability Survival improves with availability of three active drugsof three active drugs
*FOLFOXIRI
P=0.0001
Is FOLFOXIRI more active than Is FOLFOXIRI more active than 5-FU/IRI?5-FU/IRI?
Yes, including better resection Yes, including better resection ratesrates But is comparator arm inferior?But is comparator arm inferior?
More toxicMore toxic
Monotherapy
Overall survival
Integrated CRC
Capecitabine (n=603)
5-FU/LV (n=604)
13.1 13.1
0 5 10 15 20 25 30
Time (months)
Est
imat
ed p
rob
abil
ity 1.0
0.8
0.6
0.4
0.2
0
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
2,135 Untreated Stage IV patients 2,135 Untreated Stage IV patients
A: 5 FU/LV (de Gramont)A: 5 FU/LV (de Gramont)
C: FOLFOX vs FOLFIRIC: FOLFOX vs FOLFIRI
B: 5 FU/LV (de Gramont)B: 5 FU/LV (de Gramont)
RANDOMISATION
RANDOMISATION
FOCUS UK MRC CR08
IRIIRI
FOLFOX orFOLFIRI
FOLFOX orFOLFIRI
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
FOLFIRI16.7
(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 5FU TO IRI 16%
B
5FU TO FOLFOX
19%5FU TO FOLFIRI
CFOLFOX
33%FOLFIRI
FOCUS
Grothey, JCO, 2004Grothey, 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 HonkoopFLG Erdkamp, RS de Jong, CJ Rodenburg,
L Mol, NF Antonini
ASCO 2007
CAIRO study CKTO 2002-07
Arm A Arm B
Randomize
capecitabine
capecitabine +oxaliplatin
irinotecancapecitabine +
oxaliplatin
capecitabine +irinotecan1st line
2nd line
3rd line
Dose/schedule of drugsall 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
1 Rea et al. Ann Oncol 20052 Borner et al. J Clin Oncol 2002
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
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 0.0002
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
Grade 3-4 toxicities in first line
Toxicity
Arm Acapecitabine
N = 397
Arm B capiri
N = 398p 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
* 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
Tournigand et al, JCO 2006
6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7
FOLFOX4
620 pts
R
Cum. Oxali 780 1560
(%) FOLFOX4 FOLFOX7
RR 58.5 58.3PFS 9.0 8.7DDC 9.0 10.6OS 19.3 21.2G3/4 NTox 17.9 13.3
Primary endpoint
F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro,
P.Artru, C. Louvet, A. de Gramont
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.
OPTIMOX Studies
OPTIMOX-1
FOLFOX 4 until TF
FOLFOX 7 FOLFOX 7
sLV5FU2
OPTIMOX-2
mFOLFOX 7 mFOLFOX 7
sLV5FU2
mFOLFOX 7 mFOLFOX 7
CFI
Baseline Progression
t
T size
FOLFOX FOLFOX
Progression Baseline progression
Progressionat reintroduction
Chemotherapy-free Interval
Duration of Disease Control
t
T size
FOLFOX FOLFOX
PFS 1
Progression Baseline progression
PFS 2
Progressionat reintroduction
DDC = PFS 1 + PFS 2 (if no PD)
ASCO 2001, 146a
Neuropathy
Grade 1 8 %
2 21.2 % 3 2 %
Grade 1 29.4 % 2 35.3 % 3 5.9 %
Grade 1 6.8 % 2 15.5 % 3 3.9 %
Grade 1 36.8 % 2 19.2 % 3 7 %
Optimox 1 Optimox 2
After the first reintroduction
2 months after FOLFOX
Grade 1 70.7 % 2 18.1 % 3 0 %
Grade 1 70.8 % 2 16.5 % 3 0 %
During C1-C6
Chemotherapy-free IntervalChemotherapy-free interval
0 10 20 30 40 50 60 70 80 90 1000.0
0.2
0.4
0.6
0.8
1.0
OPTIMOX2 median 17 weeks
R0 surgery excluded
weeks
Probability
Duration of Disease ControlDuration of Disease Control
0 10 20 30 40 50 60 70 80 90 1000.0
0.2
0.4
0.6
0.8
1.0
OPTIMOX1 median 52 weeks
OPTIMOX2 median 39 weeks
p=0.39
weeks
Probability
Overall SurvivalOverall Survival
0 10 20 30 40 500.0
0.2
0.4
0.6
0.8
1.0
OPTIMOX1 median 26 months
OPTIMOX2 median 19 months
p=0.0549
months
Probability
Alternating vs continuous FOLFIRI in advanced Alternating vs continuous FOLFIRI in advanced colorectal cancer (ACC): colorectal cancer (ACC):
a randomized GISCAD triala randomized GISCAD trial
Roberto LabiancaOspedali Riuniti – Bergamo, Italy
Floriani I, Cortesi E, Isa L, Zaniboni A, Marangolo M, Frontini L, Barni S, Beretta GD, Sobrero A
GISCAD-Trial: Design
• Primary endpoint: OS
R
FOLFIRIFOLFIRIFOLFIRIFOLFIRI
Evaluation
4 mos
N=336
PFSMedian f-up: 30 m
Median time to PD:Arm A 6.2 mArm 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 mArm 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
Efficacy =Toxicity
Efficacy decresedToxicity =
DREAMBevacizumab
ErlotinibBevacizumab
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